Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content +++ TUMOR SUPPRESSOR GENES ++ Negative cancer regulators Cause apoptosis of DNA-damaged cells and block cell division Encode cell-cycle regulators, adhesion molecules, DNA repair enzymes, or signal transduction pathway molecules p53 most common cancer mutation, present in one-half of all human cancers; ninety percent of squamous cell carcinomas (SCCs) and in most basal cell carcinomas (BCCs) and actinic keratosis (Fig. 12-1) PTCH1 member of the patched gene family that acts as a tumor suppressor in BCC. CDKN2 mutation of this tumor suppressor leads to familial syndrome of pancreatic cancer and melanoma ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence ++ FIGURE 12-1 A model for p53-mediated apoptosis. Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ Extrinsic and intrinsic apoptotic pathways ++ Lead to the activation of the aspartate-specific cysteine proteases (caspases) that mediate apoptosis Extrinsic pathway Involves engagement of particular “death” receptors that belong to the tumor necrosis factor receptor (TNF-R) family (e.g., Fas, DR5, and PERP) Also causes the formation of the death-inducing signaling-complex (DISC) Intrinsic pathway Triggered in response to DNA damage Associated with mitochondrial depolarization and release of cytochrome c from the mitochondrial intermembrane space into the cytoplasm Cytochrome c, apoptotic protease-activating factor 1 (APAF-1), and procaspase-9 form a complex termed the apoptosome (caspase-9 is activated and promotes activation of caspase-3, caspase-6, and caspase-7) Mutation is not the only way to inactivate tumor suppressor genes; function also can be blocked by methylation of their promoter +++ ONCOGENES ++ Genes with growth-promoting activity Proto-oncogene is a normal gene that can become an oncogene due to mutations of increased expression Mutated gene causes cellular products to become constitutively active Are dominant If a normal gene (protooncogene) is present at a locus along with 1 mutated gene (oncogene), the abnormal product takes control May derive from viruses (e.g., Src, ras, cmyc) Oncogenic NRF2 mutations occur in squamous cell skin cancers Human Merkel cell polyomavirus (MCV or MCPyV) is an oncoprotein implicated in the progression of Merkel cell carcinoma (MCC) +++ CARCINOGENESIS ++ Two-hit theory of Knudsen First: inheriting a defect in the familial form (5–10% of cancers result from germ-line mutations) or exposure to a carcinogen Second: ongoing exposure to the carcinogen that acts as a tumor promoter or cocarcinogen Repeated assault on the DNA leads to mutations that cause the cell cycle to lose control Mutations from ultraviolet B (UV-B) light cause cytosine (C) to change to thymine (T) +++ AP-1 (ACTIVATING PROTEIN-1) ++ Negative regulator for procollagen transcription; blocked by retinoids Collective term referring to dimeric transcription factors composed of Jun, Fos, or ATF subunits (protooncogenes) UV-B induces AP-1 binding to DNA at the AP-1-binding site AP-1 up regulates mRNA expression for gelatinase and collagenase AP-1 blocks collagen gene expression in dermal fibroblasts AP-1 proteins regulate ... Your MyAccess profile is currently affiliated with '[InstitutionA]' and is in the process of switching affiliations to '[InstitutionB]'. Please click ‘Continue’ to continue the affiliation switch, otherwise click ‘Cancel’ to cancel signing in. Get Free Access Through Your Institution Learn how to see if your library subscribes to McGraw Hill Medical products. Subscribe: Institutional or Individual Sign In Username Error: Please enter User Name Password Error: Please enter Password Forgot Username? Forgot Password? Sign in via OpenAthens Sign in via Shibboleth