Nikolaev lecture notes

Nikolaev lecture notes - Cancer Molecular characterizations...

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1 Cancer Molecular characterizations of cancer cells shows that the mutations are often in cell cycle genes •Proto-oncogenes are normal cellular counterparts of cancer-causing mutants called oncogenes. •Proto-oncogenes promote normal cycling •Typically, mutation of one copy of the proto- oncogene to an oncogene is sufFcient to cause over-proliferation (i.e., they are dominant mutations). •Many oncogenes (mutant versions of proto-oncogenes) have been identiFed as pieces of cellular genes taken up by retroviruses. •There is positive selection for such genetic events because proliferating cells will promote viral replication and proliferation. •Tumor suppressor genes. •These genes inhibit cell-cycle progression. •Mutations in tumor suppressor genes are typically recessive because only one good copy of the gene is required to produce protein that can inhibit progression of the cell cycle. •p53 is an exception. It binds DNA as a tetramer. Mutation of one homolog can yield a "dominant negative". •±or example, the bad version of p53 might still bind the normal p53 but be defective in interacting with DNA. •Heterozygous mutant individuals are predisposed for trouble because they only require mutation of one good copy rather than two good copies of the gene.
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2 p53 transcription factor •monitors the cell and allows cells to respond to DNA damage or other stress •responds by inducing genes that delay the cell cycle (e.g., p21) to allow time to repair damage •p21 then inhibits the cell cycle by inhibiting (binding) G 1 and G 1 -S cyclin-cdk complexes •OR by inducing programmed cell death if damage is not repaired •mutated in a large number of cancers (more than 50%) implicating the lack of this checkpoint as a contributing factor to many cancers p53 transcription factor is cytoplasmic or degraded Cell cycle proceeds normally p53 transcription factor is nuclear Cell cycle “brakes” are on cdk cdk G 1 -S cyclin cyclin
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3 Nikolaev et al. (2003) Parc: A cytoplasmic anchor for p53. Cell 112:29-40 A. Background / Major Questions •HOW does p53 sense and respond to DNA damage? (i.e., How is p53 induced/ regulated?) 1. p53 is normally ubiquitinated by Mdm2 and degraded by the proteasome •DNA damage results in phosphorylation of p53 •phosphorylated p53 no longer binds Mdm2
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Nikolaev lecture notes - Cancer Molecular characterizations...

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