肿瘤发病学 教学课件.ppt

The role of p53 in maintaining the integrity of the genome. Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell cycle arrest in G1 and induction of DNA repair, by transcriptional up-regulation of the cyclin-dependent kinase inhibitor CDKN1A (p21) and the GADD45 genes. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53 triggers either apoptosis or senescence. In cells with loss or mutations of p53, DNA damage does not induce cell cycle arrest or DNA repair, and genetically damaged cells proliferate, giving rise eventually to malignant neoplasms. B, p53 mediates gene repression by activating transcription of miRNAs. p53 activates transcription of the mir34 family of miRNAs. mir34s repress translation of both proliferative genes, such as cyclins, and anti-apoptotic genes, such as BCL2. Repression of these genes can promote either quiescence or senescence as well as apoptosis. The role of RB in regulating the G1-S checkpoint of the cell cycle. Hypophosphorylated RB in complex with the E2F transcription factors binds to DNA, recruits chromatin-remodeling factors (histone deacetylases and histone methyltransferases), and inhibits transcription of genes whose products are required for the S phase of the cell cycle. When RB is phosphorylated by the cyclin D-CDK4, cyclin D-CDK6, and cyclin E-CDK2 complexes, it releases E2F. The latter then activates transcription of S-phase genes. The phosphorylation of RB is inhibited by CDKIs, because they inactivate cyclin-CDK complexes. Virtually all cancer cells show dysregulation of the G1-S checkpoint as a result of mutation in one of four genes that regulate the phosphorylation of RB; these genes are RB1, CDK4, the genes encoding cyclin D proteins, and CDKN2A (p16). EGF, epidermal growth factor; PDGF, platelet-derived growth factor; TGF-beta;, transforming growth factor-beta. Figure 1. A Continuum of Functional PTEN Loss We propose that loss of PTEN function by var