Cancer

2010-12-31T23:59:00.000-08:00

Cancers arise when cells escape normal controls on cellular proliferation. Cancer is not a single disease, rather the term encompasses a group of conditions that share the characteristic process of uncontrolled cellular proliferation of cells that are typicallly capable of local infiltration into other tissues (invasion). This propensity for invasion and migration is associated with the capacity to metastasize to sites distant from the point of origin. Benign tumors evidence as local overgrowth, but fortunately have minimal or no propensity for tissue infiltration and metastasis. Cancers originating in the same tissue/organ can vary considerably in degree of undifferentiation, sensitivity to chemotherapeutic agents, growth rate, invasiveness, and metastatic potential.

Alteration of a gene that normally controls cell growth can promote the uncontrolled growth characteristic of cancer. The normal forms of dominant genes that function in the various signal transduction cascades that regulate cell growth, proliferation and differentiation are termed proto-oncogenes, and the malignantly transformed genes are termed oncogenes.

For example, mutation in a proto-oncogene, such as a gene which encodes an intracellular signaling protein that is normally activated only by extracellular growth factors, converts the proto-oncogene into an oncogene. The malignantly transformed oncogene encodes an altered form of the signaling protein that now behaves as though activated even in the absence of growth factor binding. The malignant cell line has escaped normal gene regulation and cell cycle control mechanisms and exhibits unchecked proliferation.

A propensity for invasion and metastasis is a critical feature that distinguishes malignancies from benign tumors.

There are many excellent sites with information for those affected by cancer, so the purpose of this site, in conjunction with the companion sites, is an exploration of the cell and molecular biology of malignancy.

synonyms : cancer, tumor, malignancy, neoplasm; cancerous, tumorous, malignant, neoplastic; cancer, neoplasia, oncology.

¤¤ adenoviruses ¤ amplification ¤ carcinogenesis ¤ c-Fos ¤ c-Jun ¤ c-Myc ¤ c-Sis ¤ estrogen receptors ¤ gene amplification ¤ genetic predispositon ¤ HBV ¤ HIV ¤ HPV ¤ HTLV-I ¤ immune evasion ¤ irradiation ¤ malignant transformation ¤ metastasis ¤ mitogens ¤ mutagens ¤ MYC ¤ mutations ¤ neoplasia ¤ neoplastic mutations ¤ NF-κB ¤ non-mutagenic carcinogens ¤ oncogenes ¤ p53 ¤ proliferation ¤ proto-oncogenes ¤ radiation ¤ Ras ¤ Rb ¤ retroviral mechanisms of carcinogenesis ¤ retroviruses ¤ signaling molecules ¤ SRC genes ¤ T-antigens ¤ TP53 ¤ tumor antigens ¤ tumor suppressors ¤ tumorigenic viruses ¤ viral carcinogens ¤ v-Fos ¤ v-Sis ¤ v-Myc ¤

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tags [Cancer] [proto-oncogene] [mutation] [oncogene] [metastasis]

carcinogenesis

2010-12-22T23:06:00.000-08:00

Carcinogenesis involves damage-induced genetic alterations (mutations) that produce cancers. Mutagenesis causes genetic alterations that may, or may not, result in cancer.
Tables Malignant Transformation Oncogenes Proto-oncogenes

Many of the most powerful biological regulators of cell growth and proliferation are encoded by unstable mRNAs, which are targeted for rapid degradation by the cell. The loss of rapid degradation of these growth-promoting mRNAs can result in oncogenic transformation of the cell. Targeted degradation of proto-oncogene mRNAs and short-lived cytokines is controlled both by an AU-rich element (ARE) located in the 3' noncoding region, and by several proteins that bind the ARE sequence. Activation of the ARE for mRNA decay involves cotranslation of the mRNA by ribosomes, and employs the ubiquitin-proteasome pathway.[s]

Carcinogenesis typically results from a series of mutations that affect regulation of proliferation.
m1: inactivation of a tumor suppressor gene results in cell proliferation
m2: mutation inactivates a DNA repair gene
m3: mutation of a proto-oncogene generates an oncogene
m4: mutation inactivates more cancer suppressor genes, resulting in cancerous proliferation

Carcinogenic agents include:
Mutagenic carcinogens
Non-mutagenic carcinogens
Irradiation
Viruses (tumorigenic viruses) Transforming retroviruses and DNA tumor viruses encode oncogenes.
Genetic predisposition (Table of Hereditary Cancers)

Mutagenic carcinogens: ‘genotoxic’ carcinogens are DNA reactive and induce DNA damage. Tobacco smoke is probably the most notorious mutagenic carcinogen, producing, in addition to cardiovascular damage, cancers of the head and neck, lung, and bladder.

Non-mutagenic carcinogens: ‘non-genotoxic’ carcinogens are reported to have have significantly higher computed octanol/water partition coefficients than mutagenic carcinogens, suggesting that their ability to induce tumors may be associated with membraneous receptor sites and/or a longer residence time in the animal [r]. Estrogen can promote the growth of some breast cancers.

Irradiation:

Viruses: transforming retroviruses carry oncogenes mutated from cellular genes that are involved in mitogenic signaling and growth control. DNA tumor viruses encode oncogenes of viral origin that are essential for viral replication and cell transformation; viral oncoproteins complex with cellular proteins to stimulate cell cycle progression and led to the discovery of tumor suppressors. Viral systems support the concept that cancer development occurs by the accumulation of multiple cooperating events.[s]

Genetic predisposition: a variety of inherited genetic abnormalities render affected individuals more prone to malignancy. For example, hereditary non-polyposis colon cancer (HNPCC) is a form of colon cancer frequently associated with defects in the genes encoding MSH2 (about 35% of identified gene-defect cases) and MLH1 (about 60% of identified gene-defect cases). HNPCC is characterized by early age of onset and autosomal dominant inheritance with high penetrance. (Table of Hereditary Cancers)

∞ Cancer ∞ carcinogenesis ∞ oncogenes ∞ proliferation ∞ retroviruses ∞ signaling molecules ∞ tumorigenic viruses ∞ site map ∞

Tables Apoptosis vs Necrosis Apoptosis Cell Adhesion Cell signaling Malignant Transformation Oncogenes Proto-oncogenes Regulatory Proteins Sequences Table of Hereditary Cancers .

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cancer staging

2010-12-22T23:05:00.000-08:00

Diagnostic evaluation of malignancy includes determination of the cancer's pathology (tissue type, organ of origin) in addition to staging of the cancer to determine degree of local, regional, and distant spread. Clinical and pathological staging is important to decisions concerning therapy, and to estimating prognosis (a statistical measure).

The stage of a cancer is influenced by:
¤ the carcinoma's biological aggressiveness
¤ time elapsed before clinical/pathologic diagnosis – c, cs = clinical; p, ps = pathological
¤ time elapsed before/since institution of anti-cancer treatment
¤ the tumor's sensitivity to cytotoxic therapies

Cancers commence as in situ colonies of cells that have escaped normal cellular controls. Local overgrowth of the primary tumor (localized) is followed by local tissue infiltration, and ultimately by malignant penetration of adjacent tissues (regional), blood vessels or lymphatics, with shedding and transport of malignant cells and ultimate colonization of distant organs (distant, secondary tumors, metastases).

Staging systems reflect this biological progression and the tissue type. The system of staging employed will depend, to some extent, upon the specific form of cancer involved – whether it is a solid tumor or hematologic, whether it belongs to a group staged by a specific system, such as the Ann Arbor staging classification that is commonly employed to stage lymphomas.

Cell type and grade is used to stage carcinomas of the brain and spinal cord.

TNM system – Tumor, Node, Metastasis
T refers to the primary (solid) tumor – X (cannot be evaluated), 'is' (in situ), 0 - 4 (size/extent)
N refers to regional lymph node involvement – X, 0-4 (extent)
M refers to metastasis – X, 0 = no metastasis, 1 = metastasis

Ann Arbor System (lymphomas)
Stage I – single region, typically a single lymph node and the surrounding area
Stage II – two regions on same side of diaphragm, an affected lymph node or organ within the lymphatic system and a second affected area
Stage III – both sides of diaphragm, including organ or area adjacent to lymph nodes or spleen
Stage IV – diffuse or disseminated involvement of one or more extralymphatic organs, including any involvement of the liver, bone marrow, or nodular involvement of the lungs.

Modifications to Ann Arbor
A = absence of constitutional symptoms
B = presence of constitutional symptoms (night sweats, fevers, unexplained weight loss of >10%)
E = "extranodal" (not in the lymph nodes) or spread from lymph nodes to adjacent tissue
X = largest deposit if >10 cm large ("bulky disease"), or mediastinum is wider than 1/3 of the chest on a chest X-ray

"Staging: Questions and Answers" at the National Cancer Institute
International Union Against Cancer, TNM

c-Fos

2010-12-22T18:09:00.000-08:00

The proto-oncogene c-fos participates in cellular proliferation by encoding a transcription factor, fos that forms homodimers, or heterodimers with the proto-oncogene c-jun (as AP1). The human homolog of the fos oncogene has been mapped to chromosome region 14q21→q31, and is overexpressed in a variety of cancers. Retrovirus-associated v-fos DNA sequences were originally isolated from murine sarcoma viruses, and fos is named for feline osteosarcoma virus.

AP1 : AP1 regulation : c-fos induction : c-jun : JNK : JNKK : MEK kinase : Rac : TPA responsive element : transcription response element : TREs : v-fos :

Induction of of c-fos expression by a variety of mitogens and differentiation-stimulating agents appears to be part of a general transcriptional response to growth factors. Expression of c-fos decreases during cellular differentiation in muscle, and is inhibited by the presence of MyoD and myogenin. Expression of c-fos is stimulated before the increased transcription of c-myc, ODC, and other proto-oncogenes. [s]

Activator protein 1 (AP1) of mammalian cells is a heterodimeric transcription factor formed by c-jun and c-fos associated in a structural motif known as a leucine zipper, which is required for DNA binding. The c-jun and c-fos subunits are held together by hydrophobic interactions between leucines located every 7th amino acid in an alpha-helix region of each subunit. [] 3D model of AP1 [] diagram []

The proto-oncogene, c-jun is a cellular immediate-early gene whose expression is rapidly induced by external stimuli such as epidermal growth factor (EGF), serum, 12-O-tetradecanoyl phorbol-13-acetate (TPA), nerve growth factor, and UV. Induced transcription of c-jun is independent of new protein synthesis.

The activator protein 1 (AP1) also results from dimeric complexes between members of the atf and maf protein families. Fos and jun are the commonest constituent proteins in mammalian cells. AP-1 activity is induced by growth factors, cytokines and oncoproteins. AP1 binds to transcription response elements (TPA responsive element, TREs) in the promotor region of several genes that regulate cell proliferation, survival, differentiation and transformation. Ionic interactions between terminal clusters of arginine molecules interact with DNA. Arginine is a basic amino acid with positively charged side-groups that interact with DNA's negatively charged phosphate moieties.

Regulation of AP-1 is complex and includes factors such as the composition of the dimers, the expression level of each monomer and post-transcriptional modification of the protein. AP1 can be activated by the induction of c-jun transcription. AP-1 proteins also interact with ancillary proteins that also regulate the activity of the complex.

Phosphorylation of AP1 by Jun N-terminal kinase (JNK) occurs at the N-terminal region of the c-jun protein. JNK activation is mediated through a signaling pathway that includes the small GTPase, Rac and the protein kinases, MEK kinase (MEKK) and JNKK.

AP1 : AP1 regulation : c-fos induction : c-jun : JNK : JNKK : MEK kinase : Rac : TPA responsive element : transcription response element : TREs : v-Fos : Oncogenes: c-Fos : c-Jun : c-Myc : c-Sis : Ras : Rb : v-Fos : v-Sis : v-Myc : Tumor Suppressor Genes: TP53 :
Tables Oncogenes Proto-oncogenes Malignant Transformation Regulatory Proteins Sequences Cell signaling Cell Adhesion Apoptosis vs Necrosis Apoptosis

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c-Myc

2010-12-22T11:01:00.000-08:00

The MYC proto-oncogene encodes the transcription factor, c-Myc protein, which binds DNA to regulate transcription. c-MYC is the cellular homolog of the retroviral v-myc oncogene, which when altered by chromosomal translocation, or amplification, or when exhibiting deregulated expression, plays a significant role in mutagenesis of tumors including bladder and breast cancers. c-Myc binds with a variety of protein interactors.

The c-Myc transcription factor is a helix-loop-helix leucine zipper protein that dimerizes with an obligate partner, Max, to bind DNA sites, 5'-CACGTG-3', termed E-boxes. c-Myc also binds DNA sites that vary from this palindromic hexanucleotide canonical sequence [3]. [s]

Oncogenes: c-Fos : c-Jun : c-Myc : c-Sis : Ras : Rb : v-Fos : v-Sis : v-Myc :
Tumor Suppressor Genes: TP53
Tables Oncogenes Proto-oncogenes Malignant Transformation Regulatory Proteins Sequences Cell signaling Cell Adhesion Apoptosis vs Necrosis Apoptosis

. c-Myc Cancer Gene . Genome Biology .

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c-Sis

2010-12-22T05:16:00.000-08:00

Human c-sis/PDGF-β proto-oncogene is overexpressed in a large percentage of human tumor cells involving a growth-promoting, autocrine growth circuit. The c-sis/PDGF-β promoter contains a unique homopurine/homopyrimidine sequence (SIS proximal element, SPE), which is crucial for transciption stimulating nuclear-binding factors.[1] The human sis gene is located at 22q12.3-13.1 on the long arm of chromosome 22.

: malignant pathology : non-malignant pathology : PDGF, platelet derived growth factor : v-sis :

The v-sis oncogene of the simian sarcoma virus is a retroviral homolog of the cellular gene encoding the β chain of PDGF (9,10) The hypothesis that unscheduled production of PDGF may contribute to the growth of spontaneous tumors is supported by the finding that PDGF is frequently produced by cell lines from human tumors such as glioblastoma and fibrosarcoma (11), melanoma (12), breast carcinoma (13), lung carcinoma (14), glioma (15), esophageal carcinoma (16) and Kaposi’s sarcoma (17). Gene transfer experiments have shown that overexpression of the normal human PDGF-β gene (c-sis, proto-oncogene) can cause the generation of fibrosarcoma (18), vascular connective tissue stroma with no necrosis (19) and tumorigenic and metastatic effects (20–22). [3]

Regulation of expression of platelet derived growth factor polypeptide B encoded by the c-sis proto-oncogene is important in a number of physiological and pathological conditions.[2] Sequences upstream of the c-sis RNA CAP site respond to the HTLV-I transactivator protein to increase RNA synthesis from either the c-sis or HTLV I promoter. [2]

Platelet-derived growth factor (PDGF) is a ubiquitous, potent mitogen and chemotactic factor for many connective tissue cells. PDGF occurs as a three-disulfide-linked dimer composed of two homologous chains, α and β (1,2). The biological function of PDGF is mediated through binding to two cell surface proteins, PDGF receptors α and ß (3–5). Binding of PDGF to the extracellular part of either receptor type leads to dimerization of receptor molecules, followed by activation of the receptor protein-tyrosine kinase (6) and generation of phosphorylation-mediated signals that initiate the biological response (7,8).

PDGF has been implicated in the pathogenesis of several non-malignant proliferative diseases including atherosclerosis (23–24), fibrosis (25), restenosis following vascular angioplasty (26), giant cell arteritis (27), aseptic loosening (28) and bronchiolitis obliterans syndrome (29). [3]

: malignant pathology : non-malignant pathology : PDGF, platelet derived growth factor : v-sis :
Tables Oncogenes Proto-oncogenes Malignant Transformation Regulatory Proteins Sequences Cell signaling Cell Adhesion Apoptosis vs Necrosis Apoptosis

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Against Religious Malignancy

2008-01-01T13:30:00.000-08:00

Religion is not the only cause of malignant behavior on the planet, but it is a cause that is rooted in irrationality and too often promotes intolerance while claiming the high moral ground. A-Deistic
Adeistic
Black Out
cosmos
Eine Kleine Nattermusing
eMusings
eVolition
Galaria
Godborygmi
Godspell Follies
Gray Matters
MetaThoughts
Mimble Wimble
Naturalism
bLogodaedaly
palimpsest
Salient
Science of Evolution
Sechuam
Sintheist
Tabula Flexuosa
The Scarlet A
Weltschauung

estrogen receptors

2007-12-20T05:06:00.000-08:00

Estrogen receptors (ERs) are located in the nucleus of estrogen-sensitive tissues (breast, endometrium, brain, bone, liver, heart). When the steroid hormone estrogen enters the nucleus of receptive tissues, it forms complexes with estrogen receptors, which then bind to estrogen response elements of DNA, activating expression of genes via stimulation of co-activators. The effects of estrogen stimulation vary from one tissue to another (pleiotropy).

anti-estrogenic drugs : cancers : co-activators, co-regulators, co-repressors : ERs : pleiotropy : raloxifene : selective estrogen receptor modulators : SERMs : Tamoxifen :

Two subtypes of estrogen receptors, ERα and ERβ, are known to mediate estrogen signaling through their function as ligand-dependent transcription factors [4]. After crossing the cellular membrane, estrogens bind to receptors ERα and ERβ, leading to receptor activation.

ERs interact with cis-regulatory elements of target genes:
a) by direct binding to conserved estrogen response elements (EREs; 5'-GGTCANNNTGACC-3', where N is any nucleotide), or
b) indirectly through association with AP1 or Sp1 transcription factor complexes and their respective binding sites [5-9].

Co-activators and co-repressors complex with estrogen receptors to regulate estrogen responses [10]. Cyclical turnover of transcriptional complexes and estrogen receptors at the regulatory elements of target genes provides an additional regulatory mechanism [11-13].

Potential mechanisms for the observed pleiotropic effects of estrogens include tissue-specific distribution of co-regulators, associated transcription factors complexes, and receptor subtypes and splice variants [14]. The consequence of ER activation appears to be alterations in transcriptional activity and expression profiles of target genes. Several genes, including those for trefoil factor 1/pS2, cathepsin D, cyclin D1, c-Myc and progesterone receptor, are positively regulated by ERα [15-20].[fft-s]

Because estrogen can stimulate cellular proliferation in tissues with estrogen-receptors, it is associated with increased risk of breast and endometrial carcinomas in replicating cells. Anti-estrogen chemotherapeutic agents compete with estrogen for binding to estrogen receptors, blocking estrogen activation of oncogenes. Selective estrogen receptor modulators, or SERMs, are a class of anti-estrogen drugs that selectively stimulate or inhibit the estrogen receptors of different target tissues.

Tamoxifen was the first SERM employed as an adjuvant treatment of estrogen receptor-positive breast cancers. It exerts an antiestrogenic effect by binding to the estrogen receptors of breast cells, preventing binding to coactivators and thus preventing activation of cell proliferation oncogenes. Because Tamoxifen stimulates endometrial estrogen receptors, increasing the risk of endometrial carcinoma, its use is restricted to treatment and it is not employed for prophylaxis of breast cancers. Another SERM, raloxifene is used to prevent osteoporosis and has demonstrated effectiveness against breast cancer without the problematic endometrial stimulation of Tamoxifen.

anti-estrogenic drugs : cancers : co-activators, co-regulators, co-repressors : ERs : pleiotropy : raloxifene : selective estrogen receptor modulators : SERMs : Tamoxifen :

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gene amplification

2007-12-18T23:11:00.000-08:00

Gene amplification involves the production of multiple copies of a gene through repeated copying of the gene.

Amplification is distinct from duplication, which is precise genome doubling preparatory to cell division, and from endoreduplication, which leads to endopolyploidy. When many copies of the amplified region are produced, they can form their own small pseudo-chromosomes called 'double-minute chromosomes'.

Gene amplification results from dysfunction in malignant cell lines. However, some organisms have evolved mechanisms for gene amplification in order to provide needed gene products in large quantities. Such functional mechanisms include:
a. The elaboration of small "extrachromosomal" units that replicate to high copy number (rDNA);
b. Tandem gene duplications (DHFR);
c. Localized endoreduplication of chorion genes.

Different organisms employ different mechanisms. Sometimes, as for double-minute chromosomes and human secretin receptor gene* (HSR), more than one mechanisms is employed within an organism.

Some mutants in developmentally expressed genes of plants result from heritable gene amplification. Gene amplification can be regulated developmentally, temporally, or environmentally.

Neoplastic cells can amplify, or copy, DNA segments in response to cellular signals or environmental events. When an oncogene is included in the amplified region, then the resulting overexpression of the oncogene gene leads to deregulated cell growth. Examples include amplification of the MYC oncogene in a wide range of tumors, and amplification of the ErbB-2 or HER-2/neu oncogene in breast and ovarian cancers. Clinical treatments have been designed to target cells overexpressing the HER-2/neu oncogene protein product.

Resistance of cancer cells to chemotherapeutic agents is linked to amplification of the gene that prevents absorption of the drug by the cell. A gene called MDR, for 'multiple drug resistance', is commonly involved. The protein product of the MDR gene acts as a membrane pump that selectively ejects molecules, including chemotherapy agents, rendering the drugs ineffective.

* the human secretin receptor (hSR) is an important glycoprotein receptor involved in regulation of the secretion of pancreatic bicarbonate, water, and electrolytes.

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immune evasion

2007-12-16T11:11:00.000-08:00

Tumors employ a variety of mechanisms to evade the immune system.

Evasive mechanisms range from a passive failure to express major histocompatibility complexes (MHC) and co-stimulatory molecules 4,5 to active strategies such as the production of immunosuppressive cytokines and other factors 6,7 . Passive and active processes are also involved in the Fas counterattack.[s]

The Fas ligand (FasL, C95L) is expressed by cells of the lymphoid/myeloid series and by non-lymphoid cells, where it contributes to the 'immune privilege' of cancer cells by inducing apoptosis in infiltrating proinflammatory immunocytes 9,10 . Simultaneously, many cancer cells are relatively resistant to Fas-mediated apoptosis.

This resistance to Fas-mediated apoptosis might be a result of downregulation of Fas, or release of soluble Fas, or of abnormalities in the level of several signal transduction cascade proteins. Neoplastic Fas resistance might also result from downregulation of caspase 1, Bax or Bak, and upregulation of FLIP, FAP-1 or Bcl2. Further, some components of the pathway exhibit mutations, including Fas itself and caspase 8. Some mutations of oncogenes and tumor suppressor genes, which are commonly found in tumors, could impair Fas signaling (p53 and Ras) or could cooperate with Fas resistance (c-Myc) in certain tumor cells. Many cancer cells express FasL, so are able to counterattack and kill Fas-sensitive tumor- infiltrating lymphocytes (TILs).[s]

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metastasis

2007-12-12T19:04:00.000-08:00

Metastasis is cell motility run amok.

Malignant tumors exhibit not only uncontrolled proliferation and local invasion, but the ability to set up distant colonies. Growth and survival of metastatic tumor cells depend upon angiogenesis and the ability of tumor cells to evade detection by the immune system.

Metastasizing cells escape normal cellular adhesion mechanisms and shed from the primary tumor. Local invasion can enable the 'escapee' cells to penetrate lymphatics and/or blood vessels. Local infiltration of lymph nodes is associated with an increased likelihood of metastasis, so determination of whether or not lymph nodes are involved is important in cancer staging.

Having been transported via circulation of lymph or blood, the malignant cells invade distant tissues where they establish focal colonies of proliferating cells (secondaries). Tumors originating in certain tissues often display a propensity for metastasis to specific tissues and organs.

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mitogens

2007-12-12T15:04:00.000-08:00

A Mitogen, or somatomedin, is any molecules that stimulates a cell to divide. Most mitogens are proteins, and they stimulate signal transduction pathways that utilize mitogen activated protein kinases. Mitogens include cytokines, growth factors, hormones, neurotransmitters, cellular stress proteins, and cell adhesion ligands. For example, antigen stimulation of cell adhesion immunoglobulins triggers mitosis in B cells.

Mitogen activated protein kinases (MAP kinases) act as switch kinases that transmits information of increased intracellular tyrosine phosphorylation to that of serine/threonine phosporylation. MAPK-activated protein kinases (or MKs; formerly MAPKAP kinases) respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs.(ffta)

The signaling cascade is:
mitogen → MAPKK kinase (MAPKKK) → MAPK kinase (MAPKK) → MAP kinase (MAPK) → signaling

Among the substrates of ERK are the members of the p90 ribosomal S6 kinase (RSK) family of serine/threonine kinases (10). RSK plays an active role in nuclear signaling by phosphorylating the cyclic AMP response element binding protein (CRE-binding protein, CREB) (33), c-Fos (5), and IB (27). Phosphorylation of Bad (3, 29) and C/EBPß (4) by RSK can protect cells from apoptosis. RSK has also been implicated in cell cycle regulation. RSK phosphorylates histone H3 (25), suggesting that RSK may regulate chromatin remodeling.[s-fft]

MAP kinases are also called ERKs for extracellular-signal regulated kinases, microtubule associated protein-2 kinase (MAP-2 kinase), myelin basic protein kinase (MBP kinase), ribosomal S6 protein kinase (RSK-kinase) and EGF receptor threonine kinase (ERT kinase). Maximal MAP kinase activity requires phosphorylation of both tyrosine and threonine residues. Activators of the extracellular-signal regulated kinase family (ERKs) of MAPKs include the mitogens, Ras [fft], polypeptide growth factors PDGF, CSF-1, IGF-1, EGF insulin, PMA.

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neoplastic mutations

2007-12-11T19:11:00.000-08:00

Mutation of proto-oncogenes may convert them to oncogenes, while mutation of tumor suppressor genes may cause a loss of anti-proliferative functions.

Based on computational analysis of mutations affecting CAN-genes (candidate cancer genes) in breast and colorectal carcinomas, it has been estimated that cancers average 17 mutations (mostly SNPs) occurring within at least 90 genes [↓]. Cancers originating in the same tissue display mutation of different genes, and mutated genes contributing to breast cancer are different from genes mutated in colorectal cancers. Many of the mutated genes are involved in pathways involved in cell adhesion, cell movement, and cell signaling. Because each of the affected pathways incorporates multiple genes, mutations in different genes within a pathway could have similar consequences.

G-T mismatch in the Ras proto-oncogene can cause an alteration of the amino acid at position 12 from glycine to valine, causing the Ras oncogene-encoded G-protein to remain continuously activated when it cannot release GTP. Mutations that prevent GTP hydrolysis favor constitutive activation as RAS-GTP, Ras^D. The commonest mutations are at the 12 (Gly→Val) → GAP insensitive, and the 61 positions → stabilizing against GTP hydrolysis.

The Consensus Coding Sequences of Human Breast and Colorectal Cancers.
The elucidation of the human genome sequence has made it possible to identify genetic alterations in cancers in unprecedented detail. To begin a systematic analysis of such alterations, we have determined the sequence of well-annotated human protein coding genes in two common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ~90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention, and open fertile avenues for basic research in tumor biology. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber T, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J,
Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The Consensus Coding Sequences of Human Breast and Colorectal Cancers. Science. 2006 Sep 7; [Epub ahead of print] HHMI news.

[Analysis, identification and correction of some errors of model refseqs appeared in NCBI Human Gene Database by in silico cloning and experimental verification of novel human genes] [Yi Chuan Xue Bao. 2004] PMID: 15478601
Genetic alterations in the adenoma--carcinoma sequence. [Cancer. 1992] PMID: 1516027
Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells. [Int J Cancer. 2001] PMID: 11391615
Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. [Am J Hum Genet. 2006] PMID: 16685647
Causes and consequences of microsatellite instability in endometrial carcinoma. [Cancer Res. 1999]

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NF-κB

2007-12-11T18:13:00.000-08:00

NF-κB is an important regulator of cell proliferation, cellular survival, and the inflammatory and immune responses. Within the nucleus, the NF-κB transcription factor promotes the expression of specific genes regulated by NF-κB DNA-binding sites.

The enzyme IκB kinase (IKK) stimulates phosphorylation of two serine residues in the regulatory domain of Inhibitor of kappa B (IκB), targetting the IκB molecules for ubiquitin/proteasome degradation, and releasing NF-κB from inhibition as cytoplasm-sequestered NF-κB dimers.

Many tumor types have chronically active NF-κB, resulting from:
● mutations in genes encoding the NF-κB transcription factors themselves, or
● mutations in genes that control NF-κB activity

Several viruses, including HIV/AIDS, control the expression of viral genes through viral binding sites for NF-κB, thus contributing to viral replication or viral pathogenicity. For HIV-1, activation of NF-κB could be related to activation of the virus from a latent, inactive state.

oncogenes

2007-12-10T21:30:00.000-08:00

Alteration of a gene that normally controls cell growth can promote the uncontrolled growth characteristic of cancer. The normal form of the gene is termed a proto-oncogene, and the malignantly transformed gene is termed an oncogene.

Oncogenes: c-Fos : c-Jun : c-Myc : c-Sis : Ras : Rb :
Tumor Suppressor Genes: TP53

Damaged genes are passed down through the cancer cell line, and may be dominant or recessive genes:

Recessive: tumor suppressors, growth suppressors, recessive oncogenes or anti-oncogenes. Malignant transformation can result from genetic damage to genes coding for growth factors, growth factor receptors and/or proteins for signal transduction cascades.

Dominant: Proto-oncogenes participate in a variety of normal cellular functions, but have the potential to tranform into cellular oncogenes when damaged. Proto-oncogenes normally function in the various signal transduction cascades that regulate cell growth, proliferation and differentiation. Cellular proto-oncogenes resident in transforming retroviruses are designated as c- (cellular origin) as opposed to v- (retroviral origin). Oncogenes are malignantly transformed proto-oncogenes - table Oncogenes Proto-oncogenes

14-3-3 proteins are a family of highly conserved cellular proteins that play key roles in the regulation of central physiological pathways. More than 200 14-3-3 target proteins have been identified, including proteins involved in mitogenic and cell survival signaling, cell cycle control and apoptosic cell death. Importantly, the involvement of 14-3-3 proteins in the regulation of various oncogenes and tumor suppressor genes points to a potential role in human cancer. Tzivion G, Gupta VS, Kaplun L, Balan V. 14-3-3 proteins as potential oncogenes. Semin Cancer Biol. 2006 Jun;16(3):203-13. Epub 2006 Apr 1.

Oncogenes: c-Fos : c-Jun : c-Myc : c-Sis : Ras : Rb :
Tumor Suppressor Genes: TP53
Proto-oncogene/oncogene families ● growth factor genes ● receptor tyrosine kinases ( RTKs) ● membrane ssociated non-receptor tyrosine kinases (PTKs) ● G-protein coupled receptors (GPCRs) ● Serine/Threonine Kinases ● nuclear DNA-binding/transcription factors ●

¤ Cancer ¤ carcinogenesis ¤ oncogenes ¤ proliferation ¤ p53 ¤ retroviruses ¤ Rb ¤ signaling molecules ¤ tumor suppressors ¤ tumorigenic viruses ¤ site map ¤ Tables Oncogenes Proto-oncogenes Malignant Transformation Regulatory Proteins Sequences Cell signaling Cell Adhesion Apoptosis vs Necrosis Apoptosis

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proliferation

2007-12-09T08:09:00.000-08:00

Cellular reproduction and programmed cell death (apoptosis) are normally closely regulated within populations of cells. Cell numbers increase when cellular reproduction outpaces cell death, and such cellular proliferation is normal under some circumstances, such as clonal expansion as part of the immune response.

However, tumors arise when cell proliferation escapes normal cellular controls. Benign tumors expand locally, but lack the other defining characteristic of malignancy, which is invasiveness both locally and at a distance (metastasis).

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p53

2007-12-09T05:03:00.000-08:00

Tumor suppressor genes encode proteins that reduce the risk that a eukaryotic cell line will become tumorigenic. When tumor suppressor proteins are sequestered away from their normal functional locations within the cell by retroviral tumor antigens, the loss of their normal suppressor functions results in cellular transformation.

The tumor suppressor gene, TP53 represents an exception to an exclusive 'two-hit hypothesis' in that a single defective p53 gene is sufficient to increase susceptibility to tumorigenesis. The TP53 gene was originally identified as a major nuclear antigen in transformed cells, but mutant forms of the p53 protein interfere with cell growth suppressor effects of wild-type p53, indicating that the p53 gene product is actually a tumor suppressor. p53 is the single most identified mutant protein in human tumors, and 50% of cancers have missense point mutations in the TP53 gene.

In normal resting cells p53 is inactive and bound to the protein MDM2. This prevents both its activation and promotes p53 degradation by acting as ubiquitin ligase (Ub ligase). The transcription factor p53 is activated when MDM2 is inhibited by signaling by factors such as DNA damage. Once activated, p53 acts as a tumor suppressor gene by virtue of its apoptotic function. Active p53 induces the transcription of many genes, including Bax, which promotes apoptosis by stimulating the release of cytochrome c and apoptosome formation.

MDM2 production is induced by negative feedback from p53, and some oncogenes inhibit MDM2 activity by stimulating the transcription of MDM2-binding proteins. The Hsp90 interacts with the p53 protein in vivo. Human papillomavirus (HPV) encodes for the protein E6, which binds the p53 protein and inactivates it. This inactivation of p53, in synergy with the inactivation of another cell cycle regulator, p105RB, stimulates repeated cell division manifestested in HPV infection (a tumorigenic virus).

Damage to DNA by mutagens 'alerts' cell-cycle checkpoints, stimulating expression of ATM, CHK1, CHK2, and p14ARF proteins, and causing phosphorylation of p53 close to the MDM2 binding site. The activated TP53 gene produces several proteins, including p21 that binds to the G1-S/CDK and S/CDK complexes that are necessary for cell cycle progression G1 → S.

p53 protein suppresses tumors by:
1. activating DNA repair proteins
2. halting the cell cycle at the G1/S regulation point (DNA damage recognition) – via p21.
2. initiating apoptosis, programmed cell death, if DNA damage is irreparable.

DNA-damage checkpoints monitor DNA damage before the cell enters S phase (G1 checkpoint); during S phase, and after DNA replication (G2 checkpoint). Increased levels of CDK-molecules and cyclins are sometimes found in human cancers. CDK-molecules and cyclins collaborate with the products of tumour suppressor genes, such as p53 and Rb, during the cell cycle. The p53 protein senses DNA damage and can halt progression of the cell cycle in G1. Both copies of the p53 gene must be mutated for cycle arrest to fail completely, so mutations in p53 are recessive and p53 qualifies as a tumor suppressor gene. The protein generated by the p53 gene acts as a signal for apoptotic cell death when DNA damage is too extensive for repair mechanisms.

¤ Cancer ¤ carcinogenesis ¤ oncogenes ¤ proliferation ¤ retroviruses¤ signaling molecules ¤ tumor suppressors ¤ tumorigenic viruses ¤ Tables Malignant Transformation Oncogenes Proto-oncogenes Regulatory Proteins Sequences Apoptosis vs Necrosis Apoptosis Cell Adhesion Cell signaling □ Familial Cancer Syndromes and Tumor Suppressors □
Џ animation How Tumor Suppressor Genes Block Cell Division .

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Ras

2007-12-07T23:05:00.000-08:00

Ras genes encode proteins of the Ras superfamily, which are important molecular switches in signal transduction pathways. Ras proteins are involved in cell adhesion, apoptosis, cell migration, cytoskeletal integrity, cell proliferation, and, when unregulated, neoplasia.

activation/inactivation : amplification : DGKzeta : GAPs : GEFs : mutations : Rab: Ras superfamily : Ras : RasGAP : RasGRP : Rho : superfamily :

The superfamily includes Ras, Rho, and Rab families. The Rho family includes Rho-GTPase. [] inactive and active Ras molecular switch [] Once activated by binding to GTP (Rho-GTP), Rho GTPases interact with cellular target effector proteins to drive axonal guidance, reorganization of the actin cytoskeleton (morphogenesis, cell polarity, cell movement, and cytokinesis), regulation of gene expression, chemotaxis, cell cycle progression, oncogenic transformation, and epithelial wound repair.

Ras is a small GTPase (G-protein), a regulatory GTP hydrolase that cycles between activated (RAS-GTP) and inactivated (RAS-GDP) conformations. [] 3D inactive and active Ras molecular switch []Ras is activated by guanine exchange factors (GEFs) such as CDC25, SOS1 and SOS2, and SDC25 in yeast. The GEFs are activated by mitogenic signals and through feedback from Ras itself.

Ras is inactivated by GTPase-activating proteins (GAPs), including RasGAP. This activating protein increases the rate of GTP hydrolysis and converts Ras from the active GTP-bound conformation to the inactive GDP-bound form (releasing Pi).

Diacylgycerol kinase zeta (DGKzeta) regulates factors that promote activity of the oncogene product, Ras, the activity of which must be precisely regulated lest abnormal cellular proliferation result. An estimated 30% of human tumors have an activating mutation of the Ras gene. Guanine nucleotide exchange factors (GEFs) activate Ras by facilitating GTP binding. Abnormally high levels of the nucleotide exchange factor, RasGRP (RAS-GAP) can lead to malignant transformation. RasGRP has a diacylglycerol (DAG)-binding domain and its exchange factor activity depends on local availability of the signaling molecule DAG. Diacylglycerol kinases(DGKs) remove DAG from the cell by converting DAG to PA. DGKzeta, but not other DGKs, can completely eliminate Ras activation induced by RasGRP, and diacylglycerol kinase activity is required for this mechanism.

Ras is attached to the cell membrane by prenylation. It normally functions in pathways that couple growth factor receptors to downstream mitogenic effectors that are involved in cell proliferation or cellular differentiation. Ras activates several pathways, of which the mitogen-activated protein MAP kinase pathway is important. MAPKs transmit signals downstream to other protein kinases and gene regulatory proteins.

Mutations of Ras proto-oncogenes are common → H-RAS, N-RAS, and K-RAS oncogenes. Inappropriate activation of the Ras gene plays a key role in signal transduction, proliferation, and malignant transformation. Oncogenes such as p210BCR-ABL and the growth receptor erbB are located upstream of Ras, so their signals will transduce through Ras should they be constitutively activated. The tumour suppressor gene NF1 encodes a RAS-GAP (Ras-GRP), and its mutation in neurofibromatosis renders Ras less likely to be inactivated.

Point mutations can transform Ras into oncogenes such that its GTPase reaction can no longer be stimulated by GAP, increasing the half life of active Ras-GTP mutants. Mutations that prevent GTP hydrolysis favor constitutive activation as RAS-GTP, Ras^D. The commonest mutations are at the 12 (Gly→Val) → GAP insensitive, and the 61 positions → stabilizing against GTP hydrolysis.

Ras amplification occurs only occasionally in tumours. Unfortunately, the sequence differences between Ras proto-oncogenes and Ras oncogenes are so slight (typically single amino acid changes) that drug targetting abnormal Ras will prove very difficult.

activation/inactivation : amplification : DGKzeta : GAPs : GEFs : mutations : Rab: Ras superfamily : Ras : RasGAP : RasGRP : Rho : superfamily :

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retroviruses

2007-12-07T19:04:00.000-08:00

Retroviruses employ the RNA-dependent DNA polymerase (reverse transcriptase) within their capsid to replicate their RNA genome into a DNA intermediate, which can be incorporated into the host cell's DNA by an integrase enzyme.

Reverse transcriptase activity, exclusive of retroviral infection, occurs in most eukaryotes, generating and inserting retrotransposons into the host genome. The ability for strand displacement DNA synthesis, unassisted by other proteins, plays an important role in generation of the long terminal repeat sequences in the duplex DNA product of retroviral reverse transcription. Reverse transcriptases are found in retroviruses, retrotransposons, group II introns, bacterial msDNAs, hepadnaviruses, caulimoviruses, and HIV-1. Some 8% of the human genome is composed of endogenous retroviral material, and many endogenous retroviruses participate in control of gene transcription, cell fusion during placental development, and resistance to exogenous retroviral infection.

Right - click to enlarge image – retroviral infection and oncogenesis.
When a normal cell (1) is infected by a retrovirus (2), the viral reverse transcriptase reverse-transcribes the viral RNA into 'viral' DNA (v), which an integrase randomly integrates (inserts) into the host cell's genome (3-c-v). New viral particles are produced and shed by the infected cell (4) and some of these may contain proto-oncogene fragments of the host's genome (purple virion). Occasionally, the transducted sequence undergoes mutation (m) into an oncogene (5) that is subsequently integrated into the genome of a second normal cell (6), which becomes transformed into a tumorigenic line (7). Under the influence of other carcinogens, normal cells may suffer mutation (m) of a proto-oncogene to an oncogene (8).

Mechanisms of retroviral carcinogenesis:
1. Powerful transcriptional promoter sequences are located at the termini (ends) of the retroviral genome. These sequences are the 'long terminal repeats' (LTRs) that promote the transcription of the viral DNA into new virus particles.

Sometimes, in a process termed transduction, the process of integration causes rearrangement of the viral genome by incorporation of a portion of the host's genome into the viral genome. Occasionally, transduction provides the virus with a host gene that is normally involved in cell cycle control. The gene acquired from the host may be altered during the transduction process, in addition to its being transcribed at a higher rate by virtue of its association with the retroviral LTRs. In such cases, the transduced gene confers a growth advantage to the infected cell, causing the unrestricted cellular proliferation characteristic of tumorigenesis. These transduced host-cell-cycle genes function as oncogenes. The host gene that has been transduced is normally a cellular gene that functions as a proto-oncogene in its unmodified, non-transduced form. The genomes of transforming retroviruses contain numerous oncogenes.

2. Long terminal repeats possess powerful transcription promoting effects. Retroviral genome integration into the host genome occurs randomly. Sometimes this integration process places the LTRs close to a gene that codes for a growth regulating protein. Abnormally elevated levels of expresson of such proteins can induce cellular transformation – 'retroviral integration induced transformation'. HIV induces certain forms of cancers by this integration induced transformation process.

In most cases, cellular transformation by DNA tumor viruses result from viral protein-host protein interaction. Proteins encoded by the DNA tumor viruses are termed tumor antigens or T antigens, and they can interact with cellular proteins. The interaction of T antigens with cellular proteins sequesters the cellular proteins away from their normal functional locations within the cell. Proteins sequestered by viral T antigens are predominantly tumor suppressor proteins, and the loss of their normal suppressor functions results in cellular transformation.

¤ Cancer ¤ carcinogenesis ¤ oncogenes ¤ proliferation ¤ retroviruses ¤ signaling molecules ¤ tumor suppressors ¤ tumorigenic viruses ¤
Tables Malignant Transformation Oncogenes Proto-oncogenes

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Rb

2007-12-07T10:00:00.000-08:00

Tumor suppressor genes encode proteins that reduce the risk that a eukaryotic cell line will become tumorigenic. When tumor suppressor proteins are sequestered away from their normal functional locations within the cell by retroviral tumor antigens, the loss of their normal suppressor functions results in cellular transformation.

RB is the Retinoblastoma gene, which codes for a protein (pRb) that functions in regulation of cell cycle progression. Rb, together with p107 (RBL1) and Rb2/p130 (RBL2), is a member of the pocket protein (PP) family, which share a 'pocket' domain responsible for most of the functional interactions characterizing the activity of this family of cellular factors. Pocket proteins play crucial roles in the metazoan cell cycle through interaction with members of the E2F family of transcription factors. The pocket proteins regulate apoptosis, the cell cycle, and tissue-specific gene expression.

The pRb protein's ability to regulate the cell cycle correlates to its phosphorylation state. Phosphorylation is maximal at the start of S phase and minimal after mitosis and entry into G1. Mitogen stimulation of quiescent cells induces phosphorylation of pRB, while in contrast, differentiation induces hypophosphorylation of pRB. Therefore, the hypophosphorylated form of pRB suppresses cell proliferation.

pRb is one of the most significant substrates for phosphorylation by the G1 cyclin-CDK complexes that regulate progression through the cell cycle. As a pocket protein, pRB forms a complex with the E2F family of transcription factors. The formation of the complex inactivates E2F. Phosporylation of pRb by the G1 cyclin-CDK complex (cyclin D-CDK4/6 complex) causes pRb release from the pRb-E2F complex, freeing E2F to transcriptionally activate genes. Within the cell cycle, E2F increases the transcription of the S-phase cyclins as well as leads to increases in its' own transcription.

The c-MYC gene is an element in the growth suppressive pathway of pRB. Suppression of c-MYC expression accompanies proliferation of keratinocytes by TGF-β. Inhibition of c-MYC expression can be abrogated by introduction of vectors that express the SV40 and adenovirus large T antigens that bind pRb. Therefore, there is a link between TGF-β, pRB and c-MYC expression in keratinocytes.

Binding by hypophoshorylated pRb, which inhibits proliferation, to the transforming proteins of the DNA tumor viruses, adenovirus, SV40, polyoma, HPV, and BK accomplishes transformation of the viruses.

Various mutations result in loss of Rb function, and 30% of retinoblastomas contain large scale deletions. Splicing errors, point mutations and small deletions in the promoter regions have also been observed in some retinoblastomas.

Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins.
RB, the most investigated tumor suppressor gene, is the founder of the RB family of growth/tumor suppressors, which comprises also p107 (RBL1) and Rb2/p130 (RBL2). The protein products of these genes, pRb, p107 and pRb2/p130, respectively, are also known as 'pocket proteins', because they share a 'pocket' domain responsible for most of the functional interactions characterizing the activity of this family of cellular factors. The interest in these genes and proteins springs essentially from their ability to regulate negatively cell cycle processes and for their ability to slow down or abrogate neoplastic growth. The pocket domain of the RB family proteins is dramatically hampered in its functions by the interference of a number of proteins produced by the small DNA viruses. In the last two decades, the 'viral hypothesis' of cancer has received a considerable renewed impulse from the notion that small DNA viruses, such as Adenovirus, Human papillomavirus (HPV) and Polyomavirus, produce factors that can physically interact with major cellular regulators and alter their function. These viral proteins (oncoproteins) act as multifaceted molecular devices that have evolved to perform very specific tasks. Owing to these features, viral oncoproteins have been widely employed as invaluable experimental tools for the identification of several key families of regulators, particularly of the cell cycle homeostasis. Adenovirus early-region 1A (E1A) is the most widely investigated small DNA tumor virus oncoprotein, but relevant interest in human oncology is raised by the E1A-related E7 protein from transforming HPV strains and by Polyomavirus oncoproteins, particularly large and small T antigens from Simian virus 40, JC virus and BK virus. Felsani A,
Mileo AM, Paggi MG. Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins. Oncogene. 2006 Aug 28;25(38):5277-85.

DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1. [J Cell Biol. 1994] PMID: 8175885
Protein expression of the RB-related gene family and SV40 large T antigen in mesothelioma and lung cancer. [Oncogene. 2000] PMID: 11030152
Mechanisms by which DNA tumor virus oncoproteins target the Rb family of pocket proteins. [Carcinogenesis. 2003] PMID: 12584163
Retinoblastoma protein family in cell cycle and cancer: a review. [J Cell Biochem. 1996] PMID: 8872613
Role of the interaction between large T antigen and Rb family members in the oncogenicity of JC virus. [Oncogene. 2006] PMID: 16936750

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signaling molecules

2007-12-06T15:26:00.000-08:00

Eukaryotic cells coordinate cell growth with the availability of nutrients in their environment. Mutation of molecules involved in cell-growth signaling can result in the uncontrolled cellular proliferation that is characteristic of neoplasia. Signal transduction in cancer cells is a sophisticated process that involves receptor tyrosine kinases (RTKs) that eventually trigger multiple cytoplasmic kinases, which are often serine/threonine kinases.

A number of tumor models have identified several key cellular signaling pathways that work independently, in parallel, and/or through interconnections to promote cancer development. Three major signaling pathways that have been identified as playing important roles in cancer include the phosphatidyl inositol-3-kinase (PI3K)/AKT, protein kinase C (PKC) family, and mitogen-activated protein kinase (MAPK)/Ras signaling cascades.[↓]

ATM : ATR : DNA-PK : FRAP1 : kinases : MAPK : mTOR : Paks : PI-3-K : PIKK : PKC : Ras : receptor tyrosine kinases : serine/threonine kinases :

The mTOR protein kinase receives stimulatory signals from nutrients as well as Ras and phosphatidylinositol-3-OH kinase (PI(3)K) downstream from growth factors. Functioning as a critical growth-control node, mTOR is the 'mammalian target of rapamycin', a fungal derivative that halts protein synthesis by complexing with immunophilin FK-506 binding protein FKBP12 peptide prolyl cis/trans isomerase.

Officially termed FRAP1 for FK506 binding protein 12-rapamycin associated protein 1, mTOR is a serine/threonine kinase that regulates regulates translation and cell division. FRAP1 (mTOR) is an evolutionarily conserved member of the phosphoinositol kinase-related kinase (PIKK) family that includes DNA-PK, ATM, ATR and several other proteins. mTOR participates in the regulation of cell growth through initiation of gene translation in response to nutrients by integratating input from multiple upstream pathways, including growth factors, mitogens, leucine, insulin, and nutrients. mTOR initiates translation by activating the ribosomal p70S6k protein kinase (S6K1) and by inhibiting the eIF4E inhibitor 4E-BP1. FRAP1 is considered to be involved in numerous additional cellular functions including actin organization, membrane trafficking, secretion, protein degradation, protein kinase C signaling, ribosome biogenesis and tRNA synthesis. mTOR may contribute to the regulation of two pathways, referred to as TORC1 and TORC2 (for TOR Complex 1 and 2).

Components of the Ras and PI(3)K signalling pathways are mutated in most human cancers. The high frequency of mutations in these pathways suggests that the loss of growth-control checkpoints and the promotion of cell survival in nutrient-limited conditions may be an obligate event in carcinogenesis.[r]

p21-activated kinases (Paks) are serine/threonine kinases that function as downstream nodes oncogenic signalling pathways. Paks are well-known regulators of cytoskeletal remodelling and cell motility that promote cell proliferation, regulate apoptosis and accelerate mitosic abnormalities, resulting in tumorigenesis and cell invasiveness. Alterations in Pak expression have been detected in human tumours

Signal transduction in cancer cells is a sophisticated process that involves receptor tyrosine kinases (RTKs) that eventually trigger multiple cytoplasmic kinases, which are often serine/threonine kinases. A number of tumor models have identified several key cellular signaling pathways that work independently, in parallel, and/or through interconnections to promote cancer development. Three major signaling pathways that have been identified as playing important roles in cancer include the phosphatidyl inositol-3-kinase (PI3K)/AKT, protein kinase C (PKC) family, and mitogen-activated protein kinase (MAPK)/Ras signaling cascades. Faivre S, Djelloul S, Raymond E. New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. Semin Oncol. 2006 Aug;33(4):407-20.

~ activator ~ cadherins ¤ Cancer ¤ carcinogenesis ~ cyclin-dependent kinases ~ cytokines ~ gene regulation ¤ genetic predispositon~ growth factors ¤ oncogenes ¤ malignant transformation ¤ mitogens ¤ mutagens ¤ neoplasia ¤ non-mutagenic carcinogens ¤ p53 ¤ proliferation ¤ proto-oncogenes ~ promoters ¤ Ras ¤ Rb ~ receptor tyrosine kinases ~ regulatory proteins ~ replication ~ repressor ~ response elements ~ retrotransposons ~ restriction enzmes ~ reverse transcriptase ~ Rho GTPase ~ ribosomes ~ serine/threonine kinases ¤ signaling molecules ~ silencers ¤ T-antigens ¤ TP53 ~ transcription ~ transcription factors ~ translation ¤ tumor antigens ¤ tumor suppressors ¤ tumorigenic viruses ¤ viral carcinogens ¤

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SRC genes

2007-12-06T06:48:00.000-08:00

The SRC gene is a proto-oncogene that encodes a 60 kDa non-receptor tyrosine kinase, pp60c-src, and is the human homologue of v-Src, the transforming gene of Rous Sarcoma Virus. The cellular c-Src is linked to an array of signaling pathways impacting cellular proliferation, transformation, differentiation , survival, adhesion and migration. Overexpression and activation of c-Src is linked to the development of roughly 50% of human tumors derived from the colon, liver, lung, breast, and pancreas. Histone deacetylase (HDAC) inhibitors, which possess anti-cancer activity, repress SRC transcription in a wide variety of human cancer
cell lines.

The largest class of p-Tyr recognition domains are the family of SH2 domains that were first identified as conserved sequences in the oncoproteins Src and Fps. SH2 domains bind phosphorylated tyrosine residues in longer peptide motifs within a target proteins. SH2 domains recognize phosphotyrosine residues and SH3 domains recognise proline-rich sequences. Similar SH2 domain sequences occur in signal transduction intracellular proteins, such as Abl, ZAP70, STAT proteins, Grb2, and RasGAP.

The SRC gene is regulated by at least two promoters each of which is associated with its own distinct exon. Differential promoter usage and subsequent splicing to a common downstream exon generates Src transcripts that possess identical coding capacity yet have different 5' noncoding regions.

The SRC1α (SRC1A) promoter appears to regulate expression in many tissues, and is regulated by the Sp1 family of transcription factors. The proximal SRC1α promoter displays many hallmarks of a housekeeping gene including high GC content, in polypurine:polypyrimidine sequences (TC1, TC2 and TC3), together with multiple start sites. The factor hnRNP-K binds to the Pu:Py sequences and modulates transcriptional activity of the SRC1α promoter.

The distal SRC1α promoter is located upstream of the SRC1α promoter, is controlled by Hepatic Nuclear Factor (HNF-1), and is expressed in a much more restricted fashion than is the proximal promoter. HNF-1 is a homeodomain containing transcription factor that regulates various genes intestine and liver, so may be an important factor in regulating overexpression of SRC in malignancies that originate in these tissues.

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tags [Cancer] [Src] [oncogene]

tumor suppressors

2007-12-05T03:05:00.000-08:00

Tumor suppressor genes encode proteins that reduce the risk that a eukaryotic cell line will become tumorigenic. When tumor suppressor proteins are sequestered away from their normal functional locations within the cell by retroviral tumor antigens, the loss of their normal suppressor functions results in cellular transformation.

: APC : CBFA2T3 : Hsp90 : MDM2 : p53: PTEN : TP53 : Wnt :

Because a single normal allele will express the wild-type suppressor protein, most tumor suppressor genes are recessive, meaning that both alleles must be defective for the cell to be susceptible to tumor development.

Tumor suppressor proteins act as cell-cycle repressors and/or promoters of apoptosis through:
1. interruption of cell cycle, preventing cell division,
2. halting the cell cycle if DNA damage is not yet repaired,
3. inducing apoptosis if DNA damage cannot be repaired,
4. promoting cell adhesion and contact inhibition, which prevent invasion and metastasis.

The tumor suppressor gene, TP53 is an exception to an exclusive 'two-hit hypothesis', and a single defective p53 gene is sufficient to increase susceptibility to tumorigenesis. The TP53 gene was originally identified as a major nuclear antigen in transformed cells, but mutant forms of the p53 protein interfere with cell growth suppressor effects of wild-type p53, indicating that the p53 gene product is actually a tumor suppressor. p53 is the single most identified mutant protein in human tumors, and 50% of cancers have missense point mutations in the TP53 gene.

In normal resting cells p53 is inactive and bound to the protein MDM2. This prevents both its activation and promotes p53 degradation by acting as ubiquitin ligase (Ub ligase). The transcription factor p53 is activated when MDM2 is inhibited by signaling by factors such as DNA damage. Once activated, p53 acts as a tumor suppressor gene by virtue of its apoptotic function. Active p53 induces the transcription of many genes, including Bax, which promotes apoptosis by stimulating the release of cytochrome c and apoptosome formation.

MDM2 production is induced by negative feedback from p53, and some oncogenes inhibit MDM2 activity by stimulating the transcription of MDM2-binding proteins. The Hsp90 interacts with the p53 protein in vivo. Human papillomavirus (HPV) encodes for the protein E6, which binds the p53 protein and inactivates it. This inactivation of p53, in synergy with the inactivation of another cell cycle regulator, p105RB, stimulates repeated cell division manifestested in HPV infection (a tumorigenic virus).

Damage to DNA by mutagens 'alerts' cell-cycle checkpoints, stimulating expression of ATM, CHK1, CHK2, and p14ARF proteins, and causing phosphorylation of p53 close to the MDM2 binding site. The activated TP53 gene produces several proteins, including p21 that binds to the G1-S/CDK and S/CDK complexes that are necessary for cell cycle progression G1 → S.

p53 protein suppresses tumors by:
1. activating DNA repair proteins
2. halting the cell cycle at the G1/S regulation point (DNA damage recognition) – via p21.
2. initiating apoptosis, programmed cell death, if DNA damage is irreparable.

DNA-damage checkpoints monitor DNA damage before the cell enters S phase (G1 checkpoint); during S phase, and after DNA replication (G2 checkpoint). Increased levels of CDK-molecules and cyclins are sometimes found in human cancers. CDK-molecules and cyclins collaborate with the products of tumour suppressor genes, such as p53 and Rb, during the cell cycle. The p53 protein senses DNA damage and can halt progression of the cell cycle in G1. Both copies of the p53 gene must be mutated for cycle arrest to fail completely, so mutations in p53 are recessive and p53 qualifies as a tumor suppressor gene. The protein generated by the p53 gene acts as a signal for apoptotic cell death when DNA damage is too extensive for repair mechanisms.

The APC tumor suppressor is a component of the cytoplasmic β-catenin destruction complex, but counteracts β-catenin transactivation and histone H3K4 methylation at Wnt target genes. APC also coordinates the cyclic exchange of Wnt coregulator complexes at the DNA. β-Catenin recruits chromatin remodeling complexes, promoting transcription in the nucleus. At intercellular adherens junctions, β-catenin is an integral component of E-cadherin complexes. The opposing roles of APC and β-catenin permit a rapid coordination of gene expression and cytoskeletal organization throughout the cell in response to signaling.

The PTEN gene on chromosome 10q23.3 is 'phosphatase and tensin homolog' (mutated in multiple advanced cancers 1) and PTEN acts as a tumor suppressor gene by encoding a phosphatase that partcipates in cell cycle regulation. The encoded enzyme is phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase, and it contains a tension like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway.[eg]

Somatic mutations in the PTEN gene are among the most genetic disruptions found in human cancers, and PTEN may be the most frequently mutated gene in prostate and endometrial cancers. PTEN mutations have been identified in glioblastoma and astrocytoma, and in melanomas.

The transcriptional repressor CBFA2T3 is a putative breast tumor suppressor. A novel uncharacterized protein has been reported in association with CBFA2T3. This protein, ZNF652, contains multiple classic zinc finger domains that are predicted to bind DNA. ZNF652 exhibits a lower expression in primary tumors and cancer cell lines than in normal tissues, and is implicated in tumorigenesis. ZNF652 interacts strongly with CBFA2T3 through the COOH-terminal 109 amino acids of ZNF652. In contrast, ZNF652 interacts weakly with the other ETO members, CBFA2T1 and CBFA2T2. The transcriptional repression of growth factor independent-1 (GFI-1), an ETO effector zinc finger protein, is enhanced by CBFA2T1, and to a lesser extent by CBFA2T2 and CBFA2T3. [R= Kumar R, Manning J, Spendlove HE, Kremmidiotis G, McKirdy R, Lee J, Millband DN, Cheney KM, Stampfer MR, Dwivedi PP, Morris HA, Callen DF. ZNF652, a novel zinc finger protein, interacts with the putative breast tumor suppressor CBFA2T3 to repress transcription. Mol Cancer Res. 2006 Sep;4(9):655-65.]

CBFA2T3 (MTG16) is a putative breast tumor suppressor gene from the breast cancer loss of heterozygosity region at 16q24.3. [Cancer Res. 2002] PMID: 12183414 A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers. [Genes Chromosomes Cancer. 1998] PMID: 9591631
Isolation and characterization of a novel zinc-finger protein with transcription repressor activity. [J Biol Chem. 1995] PMID: 7673192
The catenin p120(ctn) interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor. [Mol Cell Biol. 1999] PMID: 10207085
The N termini of Friend of GATA (FOG) proteins define a novel transcriptional repression motif and a superfamily of transcriptional repressors. [J Biol Chem. 2004] PMID: 15507435

¤ Cancer ¤ carcinogenesis ¤ oncogenes ¤ proliferation ¤ retroviruses ¤ signaling molecules ¤ tumor suppressors ¤ tumorigenic viruses ¤ Tables Malignant Transformation Oncogenes Proto-oncogenes Regulatory Proteins Sequences Apoptosis vs Necrosis Apoptosis Cell Adhesion Cell signaling □ Familial Cancer Syndromes and Tumor Suppressors □
Џ animation How Tumor Suppressor Genes Block Cell Division .

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tumorigenic viruses

2007-12-05T03:03:00.000-08:00

Tumorigenic viruses are subdivided according to the nucleic acid of their genome: Transforming retroviruses carry oncogenes originally derived from cellular genes that are involved in mitogenic signalling and growth control. DNA tumor viruses encode viral oncogenes that are essential for viral replication and cell transformation; viral oncoproteins complex with cellular proteins to stimulate cell cycle progression. This mechanism led to the discovery of tumor suppressors. Viral systems support the concept that cancer development occurs by the accumulation of multiple cooperating events.

It is estimated that 15% of all human tumors worldwide are caused by viruses. The infectious nature of viruses distinguishes them from all other carcinogenic factors. Tumor viruses primarily establish long-term persistent infections in humans, and carcinogenesis is an accidental side effect of viral replication strategies. Viruses are typically not complete carcinogens, with the known human cancer viruses displaying different roles in transformation. Many years usually pass between initial viral infection and tumor development, and most infected individuals do not develop cancer, although immunocompromised individuals are at elevated risk of viral-associated cancers.[ffta]

a. RNA genomes - hepatitis C virus (Flaviviridae, hepatocellular carcinoma (HCC)) retroviruses – human T-cell leukemia viruses (HTLVs), human immunodeficiency virus (HIV, Kaposi's sarcoma, acquired immunodeficiency syndrome).
b. DNA genomes - human papillomavirus (HPV, cervical cancer), adenoviruses, Epstein–Barr virus (nasopharyngeal carcinoma, Burkitt's lymphoma, post-transplant lymphomas, Hodgkin's disease) hepatitis B virus (Hepadnaviridae, hepatocellular carcinoma (HCC)),

Right - click to enlarge image – retroviral infection and oncogenesis. When a normal cell (1) is infected by a retrovirus (2), the viral reverse transcriptase reverse-transcribes the viral RNA into 'viral' DNA (v), which an integrase randomly integrates (inserts) into the host cell's genome (3-c-v). New viral particles are produced and shed by the infected cell (4) and some of these may contain proto-oncogene fragments of the host's genome (purple virion). Often, the transducted sequence undergoes mutation (m) into an oncogene (5) that is subsequently integrated into the genome of a second normal cell (6), which becomes transformed into a tumorigenic line (7). Under the influence of other carcinogens, normal cells may suffer mutation (m) of a proto-oncogene to an oncogene (8).

Mechanisms of retroviral carcinogenesis:
First mechanism: Powerful transcriptional promoter sequences are located at the termini (ends) of the retroviral genome. These sequences are the 'long terminal repeats' (LTRs) that promote the transcription of the viral DNA into new virus particles.

Sometimes, in a process termed transduction, the process of integration causes rearrangement of the viral genome by incorporation of a portion of the host's genome into the viral genome. Occasionally, transduction provides the virus with a host gene that is normally involved in cell cycle control. The gene acquired from the host may be altered during the transduction process, in addition to its being transcribed at a higher rate by virtue of its association with the retroviral LTRs. In such cases, the transduced gene confers a growth advantage to the infected cell, causing the unrestricted cellular proliferation characteristic of tumorigenesis. These transduced host-cell-cycle genes function as oncogenes. The host gene that has been transduced is normally a cellular gene that functions as a proto-oncogene in its unmodified, non-transduced form. The genomes of transforming retroviruses contain numerous oncogenes.

Second mechanism: Long terminal repeats possess powerful transcription promoting effects. Retroviral genome integration into the host genome occurs randomly. Sometimes this integration process places the LTRs close to a gene that codes for a growth regulating protein. Abnormally elevated levels of expresson of such proteins can induce cellular transformation – 'retroviral integration induced transformation'. HIV induces certain forms of cancers by this integration induced transformation process.

In most cases, cellular transformation by DNA tumor viruses result from viral protein-host protein interaction. Proteins encoded by the DNA tumor viruses are termed tumor antigens or T antigens, and they can interact with cellular proteins. The interaction of T antigens with cellular proteins sequesters the cellular proteins away from their normal functional locations within the cell. Proteins sequestered by viral T antigens are predominantly tumor suppressor proteins, and the loss of their normal suppressor functions results in cellular transformation.

Human T-cell leukemia virus type-1 (HTLV-I) has been implicated with the etiology of adult T-cell leukemia (ATL) and certain other clinical disorders. Although the leukemogenic mechanism of HTLV-1 is not fully understood yet, the viral Tax protein is widely regarded as a key factor in this mechanism. Tax can modulate the synthesis or function of many regulatory factors which control a wide range of normal and oncogenic cellular processes and therefore, it acts as a potent oncoprotein. In the last few years, special attention has been attracted to Tax interference with the transactivation function of p53, a tumor suppressor protein that is involved in regulation of the cell-cycle and apoptosis and in maintaining the cellular genome integrity. p53 is mutated in about 60% of all human tumors. In contrast, mutant p53 is found in only small percentage of ATL patients. Nevertheless, p53 is inactive in the leukemic cells of most ATL patients and in most HTLV-1 transformed cells. By inactivating p53, Tax can immortalize the HTLV-1 infected cells and destabilize their genome. Consequently, such cells can progress towards the ultimate leukemic state by a stepwise accumulation of oncogenic mutations and other types of chromosomal aberrations. Furthermore, since p53 exists in most ATL patients in its wild type form, its reactivation by therapeutic drugs might be an effective approach for ATL therapy. Several mechanisms have been proposed so far for Tax-induced p53 inactivation. Tabakin-Fix Y, Azran I, Schavinky-Khrapunsky Y, Levy O, Aboud M. Functional inactivation of p53 by human T-cell leukemia virus type 1 Tax protein: mechanisms and clinical implications.
Carcinogenesis. 2006 Apr;27(4):673-81. Epub 2005 Nov 23.

Human Immunedeficiency Virus (HIV) is the cause of Acquired Immune Deficiency (AIDS). Although immunedeficiency syndromes were recognized prior to the discovery of HIV, the virus was discovered (isolated in '83) because an outbreak of unusual cases of Kaposi's sarcoma (since '81 in the San Francisco Bay Area).

Several viruses, including HIV/AIDS, control the expression of viral genes through viral binding sites for NF-κB, thus contributing to viral replication or viral pathogenicity. For HIV-1, activation of NF-κB could be related to activation of the virus from a latent, inactive state.

Many tumor types have chronically active NF-κB, resulting from:
● mutations in genes encoding the NF-κB transcription factors themselves, or
● mutations in genes that control NF-κB activity

Carcinogenesis of DNA viruses:
Human papillomavirus (HPV): HPV causes warts and is a risk factor for cancer of the cervix. HPV codes for the protein E6, which binds the tumor suppressor, p53 protein and inactivates it. This inactivation of p53, in synergy with the inactivation of another cell cycle regulator, p105RB, stimulates repeated cell division manifestested in HPV infection. HPV also encodes the E7 protein, which binds to the Rb protein preventing it from binding to the host transcription factor E2F. This frees E2F, which can now bind to the promoters of genes such as c-myc, stimulating the cell to enter the cell cycle.

Adenoviruses are used experimentally to induce carcinomas. Adenovirus remodels the cap-initiation complex required for translation of mRNAs. Adenovirus simultaneously inhibits cap-dependent host cell mRNA translation while promoting the translation of its late viral mRNAs during infection. Adenovirus cap-remodeling utilizes a viral protein that displaces a protein kinase from the initiation complex, and tyrosine kinase activity plays a central role in the control of late adenovirus protein synthesis. Adenovirus protein 100k blocks cellular mRNA translation by disrupting the cap-initiation complex and promotes viral mRNA translation through the alternate mechanism of ribosome shunting in a tyrosine phosphorylation-dependent manner. 100k protein interaction with initiation factor eIF4G and the viral 5' noncoding region on viral late mRNAs, known as the tripartite leader, are both essential for ribosome shunting. Heat shock induced cell stress uses heat shock proteins to inhibit cellular protein synthesis by mediating dissociation of the cap-initiation complex. Adenovirus and heat shock mRNAs utilize the altered cap-initiation complex to undergo the unusual form of translation initiation of ribosome shunting.

Hepatitis B virus (HBV) is a para-retrovirus that is associated with human liver cancer. The HBx protein is a regulatory protein that is involved in carcinogenesis and HBV infection. HBx activates Src-Ras signal transduction pathways, which are critical for HBx activation of many transcription factors, and for HBx activation of HBV reverse-transcription and DNA replication. HBx causes a loss of early cell-cycle checkpoint controls , it is probably involved in HBV pathogenesis by cytokines, and it may play a role in liver cancer caused by Hepatitis B virus infection.[s] image [] model for HBx []

The emerging p53 gene family.
Perturbation of p53 protein function is a common, if not universal, finding in human cancer. Tumor suppression by p53 is due, at least in part, to its ability to activate transcription of certain genes involved in cell cycle control and apoptosis (programmed cell death). Two additional members of the mammalian p53 family, p73 and p51, which is also known as p40, p63, KET, or p73L, were recently identified. Both of these proteins share substantial sequence homology with p53 and can, at least when overproduced, activate p53-responsive promoters and induce apoptosis. Nonetheless, data on differences between these proteins and p53 are emerging. For example, p73 is not induced by DNA damage and is not targeted for inactivation by viral oncoproteins such as simian virus 40 (SV40) T antigen, adenovirus E1B 55K, and human papillomavirus E6. In contrast to p53, neither p73 nor p51 appears to be frequently mutated in human cancers on the basis of the limited studies reported to date. Finally, unlike p53, cells produce multiple p73 and p51 isoforms as a result of alternative splicing, and production of p73 and p51 appears to be restricted to certain tissues. Additional studies are required to determine the role, if any, that p73 and p51 play in cell growth control and carcinogenesis. Kaelin WG Jr. The emerging p53 gene family. Free Full Text Article J Natl Cancer Inst. 1999 Apr 7;91(7):594-8.

¤ Cancer ¤ carcinogenesis ¤ oncogenes ¤ proliferation ¤ retroviruses ¤ signaling molecules ¤ tumor suppressors ¤ tumorigenic viruses ¤ Tables Malignant Transformation Oncogenes Proto-oncogenes

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