Tumor suppressor genes cell cycle arrest

As well as apoptosis, the p53 tumor suppressor gene causes DNA repair, blocks angiogenesis, and causes cell cycle arrest. As with oncogenes, tumor suppressor genes also have effects on cell cycle control. 

Recently, it has been found that, in addition to its detoxification function and its function as a biomarker for up-regulation of other phase II enzymes, up-regulation of quinone reductase by monofunctional inducers may play a role in the stabilization of p53, the protein product of a tumor suppressor gene, which induces growth arrest and apoptosis. Sulforaphane has also been shown to mediate growth arrest and induce cell cycle arrest and apoptosis in many cancer cell lines, including those of human prostate, colon, and T-cell leukemia origin. - The exact mechanisms, and whether all the bioactivities of sulforaphane involve the ARE, are not yet understood. 

HPV-16 encodes a set of early gene oncoproteins (E6 and E7) responsible for cellular immortalization. HPV types 16 and 18 E6 and E7 proteins are known to interact strongly with p53 and retinoblastoma (Rb) tumor suppressor gene products, respectively (2). The association of E6 with p53 marks this tumor suppressor for rapid ubiquitin-mediated proteolysis. Reduced levels of p53 prevent the cell from activating cell cycle arrest and/or induction of apoptosis in genetically mutated cells. 

Mutational inactivation of two additional important tumor suppressor genes, p53, located on chromosome 17p, and the DPC-4 (deleted in pancreatic cancer) gene, located on chromosome 18q, occur later during the adenoma-carcinoma sequence. " Normal p53 gene expression is important for Gi cell-cycle arrest to facilitate DNA repair during replication, and to induce apoptosis, an irreversible cell process resulting in cell death. Inactivation of p53 occurs in up to 75% of sporadic colorectal cancers. ... 

Fig. 15.13 Pathways of DNA damage-mediated and p53-me-diated apoptosis. The tumor suppressor protein p53 is activated by DNA damage, malfunction of signaling pathways and by various stress influences. In a transcription-dependent pathway, p53 functions as a transcription activator of various proaoptotic genes which trigger the apoptotic program and lead to cell death. Furthermore, p53 activates transcription of the inhibitor p21Klp1 leading to cell cycle arrest via inhibition of CDKs. We also know of less well characterized, transcription independent pathways (e. g. direct interaction with mitochondria) by which p53 can activate the apoptotic program.

Tumor-suppressor genes encode proteins that directly or indirectly slow progression through the cell cycle, checkpoint-control proteins that arrest the cell cycle, components of growth-inhibiting signaling pathways, pro-apoptotlc proteins, and DNA-repalr enzymes. 

Tumor suppressor genes like p53, Rb, and E2P appeared during evolution, probably to protect the integrity of the organism from uncontrolled cell proliferation within multicellular specialized tissues. This concept is supported by the observation that the respective proteins or pathways are mutated or inactivated in most human cancers. Cell cycle entry (GO-Gl- to S-phase transition) is controlled by two major pathways (1) the Rb (Rb, cy-clin Dl, and pl6 ° ) cell cycle pathway and (2) the p53/ p2iwafi Q2-S checkpoint arrest pathway. Although both pathways act largely independently, they are interconnected (Burke et al. 2005 Hsieh et al. 2002). 

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