_Dr. Powell's lecture_pmi_285_suppressor_genes_lecture_5_march_2004

_Dr. Powell's lecture_pmi_285_suppressor_genes_lecture_5_march_2004

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Tumor Suppressor Genes Jerry S. Powell March 16, 2004 Overview by the numbers cell cycle simplified cancer = a clonal proliferation p53 = Guardian of the Genome “Smoking Gun” Story
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What is cancer ? One cell (genetic change) e.g. bcr-abl = “go” 1. Proliferation = 1, 2, 4, 8, 16, 32, 64…. . 2 n n = 10, then cell number = 1,024 one cc n = 20, then cell number = 1,048,576 angiogenesis n = 40, then cell number = 1 x 10 12 Large cancer, severe leukemia n = 44, then cell number = 16 x 10 12 n = 48, then cell number = 2.5 x 10 14 = death If cell doubling takes 24 hours, then death in 48 days !
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What is cancer ? Part 2 2. Apoptosis = cell death, so if cells don’t die, then they accumulate…. Mutations of apoptosis pathway lead to accumulation of cells = cancer Tumor suppressor gene = bcl – 2 B c ell l ymphoma – “second gene looked at” Fastest increasing incidence of any tumor type in this century !
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Where do you put the brakes ? Brakes = tumor suppressor genes Controls of the cell cycle = tumor suppressor genes.
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M G2 G1 G O CELL CYCLE Inhibition: Brake = p21, its presence forms G1 and G2 “restriction points” p21 p21 S phase DNA Synthesis differentiation
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M G2 G1 G O CELL CYCLE: Brake = p21 “Go” cycle regulated by cyclins complexed with C yclin D ependent K inases p21 p21 S phase DNA Synthesis Cyclin D = regulatory unit CDK 4/6 = catalytic partner CDK 2 Cyclin E CDK 2 Cyclin A CDK 1 (cdc2) Cyclin A/B
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G O S phase DNA Synthesis Activated CDKs phosphorylate Rb protein ( retinoblastoma protein ), releasing E2F How important is Rb ?? Rb binds E2F transcription factors. E2F transcribes lots of responder genes, cyclin E Rb/E2F
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CELL CYCLE: absence of p21 Cyclin D CDK 4/6 Rb E2F Rb p E2F Gene transcription ++ ++ “Go” cycle
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What happens without Rb ? Cyclin D CDK 4/6 Rb E2F Rb p E2F Gene transcription ++ ++ 2 copies = normal 1 copy = “at risk” 0 copy = tumor “No brake”
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1979 - discovered, Arnold Levine’s lab 1989 - mutations in p53 linked to cancer over 10,000 mutations in humans to clams Other cancers caused by alterations in proteins that modify p53, or transmit information to/from p53. p53 is “the most important tumor suppressor”
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_Dr. Powell's lecture_pmi_285_suppressor_genes_lecture_5_march_2004

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