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Bio_218_gen_basis_cancer_lec_2

Bio_218_gen_basis_cancer_lec_2 - Proto-oncogene Tumor...

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Proto-oncogene Tumor suppressor Gain of function mutation Loss of function mutation Tumorigenesis p53 - the famous tumor suppressor that was mistaken for an oncogene… Now know that p53 acts as a watchdog in the cell - can activate cell cycle arrest , or apoptosis , in cells exposed to many different stresses (typically DNA damage or oncogene activation). > 50% of all human tumors have inactivating mutations in p53 - probably others have mutations elsewhere in p53 pathway. Clearly, dysregulation of p53 activity an advantage to tumor cells... Any gene that fits these criteria can arguably be called oncogene or TS - (although some insist that the mutations should be seen in tumors for the designation…). Probably hundreds - many will have cell type specific or small quantitative effects
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p53 as oncogene…? 1970s - immunoprecipitation of large T antigen from cells transformed by SV40 brought down a host protein (53 kD). Antibodies made against p53 showed it was expressed at very low levels in normal cells, but abundance was greatly increased in SV40 transformed cells High p53 protein levels seen in tumors caused by viruses, chemical carcinogens, as well as spontaneous tumors and transformed cell lines Moreover - t 1/2 of p53 in normal cells ~20 minutes - in tumor cells t 1/2 on the order of hours Looks like an oncoprotein - overexpression and stabilization associated with transformed state….
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cDNA and genomic sequences cloned in early 1980s - could now test oncogenic activity directly Some p53 cDNAs could immortalize cells in culture, and could enhance transformation by activated Ras * - fits model so far… Problem (~1989) - when wild type p53 was transfected into cells - not only didn’t immortalize, but had opposite effect! Blocked cell cycle in late G1, interfered with transformation by oncogenes. Also, in certain murine and human tumors - both alleles found to be mutant (missense mutations or complete loss) * turns out the “oncogenic” p53 cDNAs contained important mutations... How can p53 have characteristics of both oncogene and tumor suppressor??
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Protein works as a tetramer - four identical subunits. Inactivation of one allele through missense mutation can inactivate almost all p53 complexes in cell...
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