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Lecture 20

MCB 4010 Lecture 20: Oncogenes and Tumor Suppressor Genes

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Molecular and Cellular Biology
MCB 4010

MCB 4010 Cancer Lecture 20 Lecture 20 – Oncogenes and Tumor Suppressor Genes Oncogenes and tumor suppressor genes Oncogenes: - Normal function of proto-oncogene is to promote cell division and survival - rasD, EGFR/HER2, c-myc, Bcl-2, Bcr/Abl Tumor suppressor genes - normal function is to inhibit cell division and survival - Rb, p53 Proto-oncogenes can be activated by genetic changes affecting either protein expression or structure Point mutation producing a hyperactive protein – Ras - Initial characterization of tumor derived H-ras and normal H-ras genes revealed they were the same size and had identical restriction enzyme digestion patterns - Hybrids were made and tested in transfection/transformation assays - Localized mutated region to 350 bp fragment - Fragment sequences – identified single point mutation (G12) MCB 4010 Cancer Lecture 20 - RTKs → Grb2 → Sos → Ras → Raf → MEK → ERK Gene amplification resulting in protein overproduciton – HER2 - HER1 (erb-1, EGFR) overexpressed in ~30% of carcinomas - HER2 (erb-2, neu) overexpressed in 30% of breast cancer o Overexpression due to gene amplification o Overexpression results in elevated AKT and MAPK signaling - Herceptin: anti-HER-2 specific humanized monoclonal antibody o Promotes receptor internalization o Reduces AKT and MAPK signaling o Increases radiation response - Limitations of antibody therapeutics for HER1/2 o Limited tissue penetration o Not effective in tumors with receptor ectodomain truncations o Other genes in same locus are also amplified Deregulation of Myc expression can occur by many mechanisms Myc discovery: transforming sequence from MC29 avian tumor virus (V-gag-myc) homologous to cellular gene which was named myc (virus induced myelocytomatosis leukaemia) - Initial characterization showed that c-myc sequence in tumor cells was identical to sequence in normal cells - Myc can be overexpressed due to retroviral transduction, retroviral promoter insertion, chromosomal translocation or gene amplification - Overexpression of c- myc leads to growth factor independent cell cycle progression Mitogenic stimulation of quiescent cells leads to increased c-myc expression - c-myc mRNA and protein have extremely short half lives - c-Myc can also be overexpressed in tumor cells as a result of mutations affecting signaling pathways controlling c-myc transcription Overexpression of c-myc due to gene amplification or chromosome translocation c-myc proto-oncogene amplification - defective DNA repair sites of double stranded breaks MCB 4010 Cancer Lecture 20 c-myc proto-oncogene translocation - c-myc gene placed near immunoglobulin enhancer - enhances c-myc expression Control of R-point transition by c-myc - Myc/Max heterodimers bind promoters of genes required for G1/s transition - Myc/Max: transcription activator o Cyclin D/CDK4 → Rb phosphorylation o E2F → R point transition o CSF (Cul1) → p27 degradation - Myc/Miz: transcription repressor o P15, p21 synthesis repressed → relieve CDK inhibition c-myc controls both cell proliferation and apoptosis Rat-1 cells arrest when placed in low serum - reduced live cell number count - reduced % of cells in S phase Rat-1 myc cells appear to stop growing in low serum - reduced live cell numbers - however, no reduction in % of cells in S phase - forced expression of myc induced apoptosis when cells lacked growth factor signaling c-myc stimulates prolimeration and primes cells for apoptosis Safeguard against cancer - proliferating cells are primed to die - proliferation requires growth factor regulated expression of anti-apoptotic proteins (Bcl- 2) to suppress apoptosis - death occurs if cells migrate far from survival factors Obligate combinatorial signaling network - P1 without P2 = death - P2 without P1 = senescence - Growth occurs only when the proliferative pathway of program 1 and the anti-apoptotic pathway of program 2 are predominant - Downregulated c-myc upregulates ARF o MDM2 repressed → p53 stabilized → apoptosis MCB 4010 Cancer Lecture 20 Translocation producing constitutively active receptor kinase – Met - Gene encoding growth factor receptor becomes fused to a gene encoding a protein that normally oligomerizes forming a constitutively active receptor - Met receptor normally binds hepatocyte growth factor (HGF) o Fusion with Tpr (translocated promoter region) forms fused protein that is constitutively dimerized and has constitutive tyrosine kinase activity Translocation producing constitutively active non-receptor kinase – Bcr/Abl - 1960 - small Ch.22 (Philadelphia chromosome) associated with 95% of all CML (chronic myelogenous leukemia) 1 - 1972 - Ph chromosome results from a reciprocal translocation between Ch 9 and 22 - 1982 - fused region sequenced - Ch 9: ABL, the human homolog of mouse c- abl proto- oncogene (Abelson mouse leukemia virus) and Ch 22: the breakpoint cluster region - 1984 - Bcr/Abl protein is a constitutively active tyrosine kinase. Overexpression causes leukemia in mice - Bcr/Abl activates several signaling pathways o PI3 kinase, Jak-STAT, Ras etc. Small molecule kinase inhibitors for cancer therapy Gleevec: small molecule inhibitor of the Abl tyrosine kinase – binds the kinase domain - Relatively specific for Abl kinase (targets 4 of 90 human tyrosine kinases) - Inhibits the growth of CML cells in vitro (triggers apoptosis) – effective dose 40 nM - 1998: clinical trials for early stage CML showed positive response in 90% of cases - relapse risk 10%/year due to mutations in the Abl kinase domain - acquired point mutations interfere with binding of Gleevec to the catalytic cleft - in some cases resistance was acquired due to amplification of the BCR-ABL gene Tumor suppressor genes – Caretakers and Gatekeepers - In tumor suppressor genes identified in a number of rare hereditary cancer syndromes: Caretakers: control rate of mutation (DNA repair) - Bloom syndrome: repair double strand breaks - Xeroderma pigmentosum: nucleotide excision repair - Ataxia-telangiectasia: monitor DNA damage Gatekeepers: directly con
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