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tumor suppressors

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 G1S.

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
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Џ animation How Tumor Suppressor Genes Block Cell Division .



Blogger DANIEL said...

the text is interesting as the proteins act as tumor suppressor interrupts the development of tumor growth or interrupts the normal cell cycle and reproduction and how these proteins act in the Soft Cialis human body

6:27 PM  

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