33 12 loss of apoptosis control leads to survival of

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12 Loss of apoptosis control leads to survival of damaged cells Gain-of-function: Overexpression of Bcl2 observed in lymphoma 34 Loss of function mutations in both copies of tumor suppressor genes is observed in cancers Retinoblastoma Tumor of the retina Initiating mutation from mutations in both copies of the Rb loss-of-function=tumor suppressor Rb normally function to suppress the transcription of cell cycle genes and thus inhibits cell proliferation 35 DNA damage checkpoint Which factors are likely tumor suppressors? 36
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13 Evidence for a multi-hit model of tumor initiation and progression Cancer incidence increases with age 37 Cells have many safeguards to prevent unregulated cell growth Combinations of loss-of- function (tumor suppressor) and gain-of-function (oncogenes) mutations required to induce tumor formation and progression Multi-hit model of cancer 38 Evidence from model organisms for the multi-hit model: Multiple mutations can synergize during tumor progression Mice overexpressing myc or expressing mutant ras develop tumors Mice with both mutations develop tumors faster 39
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14 Types of DNA lesions that lead to cancer Point mutations single mutations like in oncogenes mutations in both copies of gene like in tumor suppressors Chromosomal translocations generation of “new” chimeric proteins with new functions- often results in protein lacking normal regulatory region expression of a pro-proliferative or pro-survival gene under a highly expressed promoter- unregulated expression Gene amplification Increased copy number of a gene resulting in higher than normal expression levels 40 BCR-ABL translocation leads to chronic myeloid leukemia Abl is a tyrosine kinase that normally activates signaling molecules resulting in cell proliferation BCR-Abl fusion protein is lacking the negatively regulatory elements of the Abl kinase, thus the fusion kinase is constitutively active 41 Drugs targeting of BCR-Abl fusion protein specifically block CML proliferation 42
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15 Global Therapies vs. Targeted Therapies Global Therapies- controlled poison cytotoxic treatments like chemotherapy and radiation therapy Advantage- Potent Disadvantage- Harsh side-effects Targeted- molecule specific Molecule specific inhibitors like gleevac or statins Advantage- Specific Disadvantage- Not necessarily potent enough when side effects are minimized; often tumors have more than one problem 43
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