S93: The Cell Cycle and Cancer!Main Ideas!- Checkpt controls make sure that each phase of the cell cycle is properly completed before the next stage is initiated!- In cancer, many of these checkpts inactivated, which helps them accumulate the mutated genes and altered karyotypes that propel neoplastic growth!- Deregulation of the restriction point controls (esp. Rb, p53) accompanies the formation of most types of cancer cells!- Rb controls passage by binding to the E2F txn factors and preventing their ability to activate critical genes needed for cell cycle progression!- Cells attempt to block the development of cancer by activating p53, which can cause cells to enter quiescence or apoptosis.!- p53 turns over rapidly and this can blocked when signals indicate the cell is under stress!- the process of tumor formation is a complex one of multiple steps involving multiple genetic alterations!- the complexity of this process is reflected by the long time periods req. for most cancers to develop!- these changes involve both the activation of oncogene and the inactivation of tumor suppressor genes!!1) Understand how cells normally limit responsiveness and growth. - Normal cells have many ways to control cell proliferation - Contact inhibition: cells don't pile up on each other!- Req. for mitogen and GF stimulation to syn. the D cyclins!- Replicative senescence: a state where cells are alive, but UNABLE to divide because of an 'aging' process that likely involves telomere shortening!- Checks to prevent overstimulation!- Desensitization to mitogen signaling!- activation of p53!- One check to overstimulation by mitogens in normal cells: increased p53!- Unknown mech: excess mitogen stimulation --> production of more Arf in normal cells --> Arf sequesters Mdmd2 E3 ubi ligase so it CAN'T ubi p53 --> p53 is stabilized and can cause cell cycle arrest or apoptosis!- In cancer cells, this mech. is often inactivated due to muts in essential components of this pathways, like Arf or p53!!!!!!!!!!!!!2) Compare and contrast the causes and effect of mutations in proto-oncogenes and in tumor suppressor genes.!- Mutation of Critical Genes - Overactivity/dominant/gain of function: this mutation event is a proto-oncogene, typically a GAIN of function, so you only need to have 1 to have the effect= dominant function in the cell!- Underactivity/recessive/loss of function: tumor suppressor gene -- loss of function, mut in 1 allele doesn't typically lead to problems= recessive function in cell (exception= p53) !- Cells can overcome their control systems!- Cancer from deregulated cell proliferation: alterations that get around the need for mitogens or target the G1 checkpoint!- produce own mitogens!- activating muts in proto-oncogenes (ex. RTKs and their receptors, Cyclin D, Ras, PI 3-kinase, related signaling pathways)!- Muts that increase expression of Myc or AP-1!- Inactivating muts in tumor suppresors (ex. Rb, CKIs, PTEN, p53, TGFB)!- Creation of new signaling proteins thru fusions!- Cancer from dereg cell survival: muts that suppress apoptosis!- Activating muts in PI 3-kinase cascade, Bcl2!- Inactivating muts in PTEN, p53, Bad!- Some alterations short-circuit the need for mitogens to start the cell cycle by altering the GF receptors!- Muts in genes encoding GF receptors can cause changes in the R's so they dimerize and are active WITHOUT mitogen. These incl. aa substitutions (red dots) or truncation (cutting off) external domain - Also, too much R can be made - Can get around the need for mitogens by acquiring autocrine signaling!- Cancer cells can make their own mitogens and thus set up autocrine signaling that stimulates cell prolif!- Likely thru epigenetic mechs!- Chromosomal Translocations can create fusion proteins w/oncogenic properties!- the Philadelphia chromosome is created by a reciprocal translocation of tips of chroms 9 and 22!--> gen. the BCR-ABL fusion protein= a constitutively active tyrosine kinase!- Kinase phosphorys and activates many signaling proteins, incl. JAKs!- If occurs in bone marrow --> chronic myeleogenous leukemia (CML)!- Imatinib (Gleevac) specifically targets the ABI kinase active site, 1st cancer drug targeted to a signaling protein unique to cancer cells !- Genetic mechs for inactiving a tumor suppressor gene!- esp. w/tumor suppressor genes, the 2nd change/hit can be epigenetic where that gene is silenced ! 3) Describe how mutations in p53 and Rb contribute to
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