How dominant-negative mutations caused p53 to also be identified as an oncogene,”most p53 mutations eliminate DNA binding and destabilize the protein (mutant protein is functionally “”invisible””)BUT since p53 functions as a tetramer, some mutations that eliminate p53 function (transactivation), also inactivate tetramers containing only 1 mutant subunitIf cells contain equivalent amounts of wild-type and d-n mutant forms of p53 protein

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Cytochrome P-450,”enzymes that modify smoked meat compounds(why liver cancer is so prevalent)liver exposed to higher concentration of these compounds than other organs and tissuesIntestinal epithelial cells (exposed to everything that goes through our bodies)cytochrome P-450 convert, guanine forms covalent adduct that can only be repaired by DNA repair enzymes

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With exposed regions of DNA…,”only have exposed DNA very transiently during transcription and replicationModified guanine will distort double helix, will be enough to activate themRNA polymerase can’t get through them, going to have exposed regions of DNA single stranded DNA activates kinasesKinases have two main targets to phosphorylate:1) P532) checkpoint 1 or 2Going to see:1) stop cell cycle2) activate expression of gene3) if none work

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Myc,”translocation of c-myc gene from chromosome 8 to 14 places it under transcriptional control of a strong immunoglobulin gene transcriptional enhancer(don’t need growth factor, elevated expression…)overexpression of c-myc in these B cells causes Burkitt’s lymphomagoing to be self-sustaining b/c last step is activatedlast step in RTK signaling before activating Cyclin D (trips the cycle out of G0), transcription activated, make a proteindifficult to target(activate transcription of myc, RNA out of cytoplasm, comes back into nucleus, that activates Cyclin D–>once synthesis begins

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MAPK,”Mitogen-activated Extracurricular signal-regulated Kinasedual-specificity Kinase (threonine, tyrosine)when activated, will rephosphorylate Rafcomes back and shuts Raf back off, goal is to not let proliferative pathway go any further than it already is(If MAPK can phosphorylate, it will shut off)when active, it forms homodimer sort of like PKA, it phosphorylates actual proteins in the cell, a huge number, only looking at a small subset necessary for the cell to proliferateand can come right to the nucleuswithin the nucleus, cohort of DNA transcription factors already there

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