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Published byŌἈμώς Λαμέρας Modified over 6 years ago
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Genetics Of Cancer Regulation of cell proliferation and cancer
Oncogenes and Tumor Suppressor Genes identified by turmorigenic viruses Oncogenes identified by DNA transfection experiments Tumor suppressor genes revealed by hereditary cancers Multiple mutations are required for cancer cell formation
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Terminology Cancer – abnormal, rapidly growing, cells
Malignant cancer – Named by tissue of origin: Sarcomas – bone, muscle, connective tissue; Carcinomas – epithelial tissue; Leukemia – blood; Lymphoma – lymphatic Two Types of mutations that contribute to cancer cell phenotype: Oncogenes – gain of function in genes that promote cell proliferation positive regulators of proliferation cell cycle genes differentiation genes negative regulator of apoptosis (cell death) Tumor suppressor genes – loss of function in genes that inhibit cell proliferation negative regulators of proliferation (cell cycle, differentiation) activators of apoptosis regulators of genomic integrity DNA Repair genes cell cycle checkpoints Cancer can be sporadic (no family history) or hereditary (inherited pre-disposition)
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Positive-acting signaling pathways controlling cell proliferation
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Negative-acting signaling pathways controlling cell proliferation
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Mutations in signaling pathways increasing cell proliferation
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Regulation of Cell Proliferation: Cell Cycle Control
Cdk4/Cyclin D Cdk4/Cyclin D Cell Proliferation Signals Most non-proliferating cells are in G0 At end of mitosis, cells enter either G0 in the absence of cell proliferation signals G0 is similar to G1 in proliferating cells except that genes required for S phase are not expressed Regulation is at the level of regulation of transcription The decision to divide or not is made here for most mammalian cells Regulation of G0 to G1 and G1 to S altered in many cancers Cdk4/Cyclin D, Rb and E2F are key regulators of G0 to G1 to S and are mutated in many cancers Positive-acting regulators: Cdk4/Cyclin D, E2F, Cdk2/Cyclin A Negative-acting regulators: Rb, inhibitors of Cdk4/Cyclin D Cdk2/Cyclin A DNA polymerases Etc…
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Regulation of Cell Proliferation: Proliferation Signaling Pathways
Similar to figure 15-13 in text Positive-acting regulators: SH2 proteins Receptor Tyrosine Kianse (Sev), SH2/SH3 adaptor (Drk), GNRP (aka GEF) SOS, Ras Negative-acting regulators: Ras GAP Activation of MAP Kinases Transcription of Genes that Promote Cell Proliferation
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Regulation of Cell Proliferation: Cell Cycle Checkpoint Pathways
Cdk4 Cyclin D Negative-acting regulators of cell proliferation: p53, p21
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Regulation of Cell Proliferation: Apoptosis Signalling Pathways
Activation Of Apoptosis Bcl-2 Inhibition Of Apoptosis Positive-acting regulators of apoptosis: Fas Ligand, Fas Receptor, Apaf, Caspase proteases Negative-acting regulator of apoptosis: Cell Survival Receptor, Bcl-2 Apoptosis
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Discovery of Oncogenes and Proto-oncogenes in animal RNA tumor viruses
Formation of RNA Tumor Viruses: WT RNA virus Integrate into host genome Pick up part of host proto- oncogene RNA tumor virus with oncogene V-erbB: constitutively active because of loss of regulatory domains Other functions intact (signaling) Positive-acting pathway for survival and proliferation Contributes to loss of control of cell proliferation Proto-oncogene to oncogene: gain of function mutation - hypermorph or neomorph
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Retroviral Oncogenes and Tumors
Rous sarcoma virus - First oncogene… Mechanisms of gain of function mutations include: Loss of regulatory domains Other mutations in coding sequence Increase in copy number Increase in transcription levels not a kinase…
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Identification of Human Oncogenes by DNA Transfection Experiments
Tumor Cell DNA + Rodent Fibroblasts ID transformed cells by colony = loss of contact inhibition = transformed phenotype Rodent colony DNA + Rodent Fibroblasts After several passages, screen transformed Rodent colony DNA with Human Alu DNA Human DNA contains oncogene N-ras discovered by this procedure
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Ras and the Ras Oncogene
Mutation in coding sequence causing gain of function: constitutively active Ras Constitutively activated pathway promoting cell survival and proliferation
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Discovery of Oncogenes by Translocations
Philadelphia Chromosome – t(9;22)(q34;q11) Chronic myelogenous leukemia (CML) First defined translocation associated with cancer Protein fusion ; BCR::ABL (break point cluster gene::ABL protein kinase) Other leukemias caused by translocation that fuse strong promoters to regulatory genes: Fusion to bcl-2 – anti-apoptosis… (next slide) Fusion to cyclin D1 – positive cell cycle regulator Abl kinase is now constitutively active, promoting cell survival and proliferation
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Discovery of Oncogenes by Translocations
B-cell lymphomas Gene Fusion: Antibody gene enhancer fused to bcl-2 promoter and transcribed region
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Discover of Tumor Suppressor by Hereditary forms of Cancer
Autosomal dominant mutation Mapped to Rb locus, gene cloned and studied – this is why we know about regulation of G1 to S in mammals Dominant due to Loss of Heterozygocity: Recessive at the level of the cell – heterozygotes are wild type Dominant at the level of the organism Wild type allele is lost by one of several mechanisms (two slides ahead) Highly Penetrant (almost 100%) with obvious familial basis
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Retinoblastoma also occurs sporadically
Requires two mutations Less frequent Note: mechanism for tumor promotion by some DNA tumor viruses involved inactivation of Rb: DNA Tumor Viruses Transforming Genes (transformation = loss of growth control) Human papilloma virus (HPV) E7 protein = transforming gene E7 binds and inactivates pRB Some associated with cervical cancer Risk of tumor promotion in HPV virus types correlates with strength of E7 binding to pRB binding
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Mechanisms for LOH ND = nondisjunction
NDR = nondisj + reduplication of remaining chromosome REC = recombination Other = point mutations, deletions, gene conversions (both Rb alleles identical)
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Multiple mutations are required for conversion of normal cell to cancer cell
Development of cancer from colon polyps involves a series of Mutations Inheritance of Mutations in APC gene increase risk of colon cancer Common sequence of mutations: LOH for APC: mutation of RAS; LOH for p53; others; malignancy Familial Adenomatous polyposis or Adenomatous Polyposis Coli Hundreds of polyps in colon by young adulthood (as opposed to HNPCC) Linked to cytological defect at 5q = APC gene APC gene codes for 300kD beta-catenin, which is involved in cell to cell contact LOH for APC is associated with development of malignant tumors from benign polyps APC, p53 = tumor suppressor genes HNPCC = hereditary non polyposis colon cancer Inherited mutation in DNA mismatch repair genes Promotes mutation that lead to colon cancer, other cancers…
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