Skip to Main 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.

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 the expression and ...

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.