p53
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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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 .
▲ Top ▲