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11 Cards in this Set
- Front
- Back
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What are the key features of cancer cells? |
- Uncontrolled proliferation - angiogenesis -chemo/radiotherapy resistance - evasion of apoptosis - invasion and metastasis |
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What are some factors responsible for the progression and development of cancer? |
- oncogenic activation of proto-oncogenes - overactivation of GFs or proliferation proteins - mutations in ant/pro-apoptotic proteins - mutations in key regulatory proteins (tumour suppressor genes) |
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What is the function of p53? |
- Tumour suppressor gene - Works as a TF (of Apaf1, Fas, Bax, BCL2 etc. mostly intrinsic pathway proteins) - Can bind at least 300 promoter regions - As result of stress or damage p53 can arrest cell cycle or induce apoptosis - mutations lead to cancer |
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What is the structure of p53? |
- has 4 domains - Trans-activation region - DNA binding domain - Oligomerisation domain - regulatory domain - binds DNA as a tetramer |
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How are protein levels of p53 regulated? |
- regulated by degradation not synthesis - Main regulator - MDM-2: 1) proteosome-mediated degradation 2) inhibits transactivation domain 3) transports p53 into cytoplasm 4) preventr transcriptional activity) |
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There are three independent molecular pathways that signal cellular distress to p53: |
- DNA damage - indicated by kinases (phosphorylation of p53) - Oncogene activation - Arf sequesters MDM2 - Cell stress - - kinase phosphorylates p53 |
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Mutations of p53 are the most common mutation found in tumours. On what domain ar they usually found? |
- DNA binding domain - however, there are a range of synthetic peptides that can restore mutant p53 transcriptional activity e.g. PRIMA-1 |
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What mutations affecting the extrinsic pathway can lead to cancer?
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- FAS and TRAIL receptor mutations - Caspase-8 (various different mutations of different effect; epigenetic silencing of gene promoter) |
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What mutations affecting the intrinsic pathway can lead to cancer? |
- p53 - upstream regulators or targets - MDM-2 - BCL-2 oncogenic activation = decreased apoptosis (lung, breast, gastric cancers); deletions in BAK or BID - Apaf-1 = decreased expression in melanoma - XIAP - increased expression in many cancers - Growth factor (survival) receptors - resutls in over stimulation of PI3-kinase/Akt pathway - inactivation of BAD = suppressed apoptosis |
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Anti apoptotic strategies used by cancer cells (2): |
- decrease in levels or activity of pro-apoptotic molecules - increase in levels or activity of anti-apoptotic molecules |
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Antiapoptotic drugs strategies: |
- activate caspases - inhibiting XIAP (overexp in many cancers) with polyphenylureas - target BCL-2 family - use TRAIL - differential activity of killin in normal cells vs cancer cells - 80% of cancer is sensitive to TRAIL |
