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ERBB1 ERBB2 EGFR FLT3 RET PDGFRB KIT SIGNAL TRANSDUCTION RAS KRAS HRAS NRAS ABL BRAF b-catenin NUCLEAR REGULATORY MYC CMYC NMYC LMYC CELL CYCLE REGULATORS Cyclin D Cyclin E CDK4
Encodes B chain of PDGF. Overproduced in Astrocytoma, osteosarcoma. Cells express PDGFR (Autocrine) FGF homologue. Overexpressed in GI tumors. FGF homologue. Amplified in Bladder, Breast, Melanoma EGF homologue. Overexpressed in Astrocytomas, Hepatocellular carcinoma Overexpressed in Thyroid Cancer EGFR. Overexpressed in 80% squamous cell lung, 50% glioblastoma, 80-100% H/N tumors. “HER2/neu”, EGFR. Amplified in 25% breast cancers. ‘’ Point Mutation in tyr-kinase receptor myeloid luekemias (15;17) and CN AML (bad prognosis) Germline inheritance Point Mutation in tyr-kinase receptor MEN2A (extracellular), MEN2B (cytosolic) MEN2A Thyroid, adrenal, parathydroid. MEN2B Thydroid, adrenal. . Overexpression glioma Translocationleukemia Receptor tyr-kinase for stem cell. Point mutation GI tumors (90%) GTP binding domain. Point mutation is most common abnormality of proto-oncogenes in all human tumors (15-20%) Carcinomas of colon, lung, pancreas Bladder tumors, kidney tumors. Hematopoietic tumors. Non-Receptor tyrosine kinase. Translocation from Chromosome 9 in CML, ALL RAS signal transduction. 80% of nuevi, 60% of melanomas. Part of WNT signaling. Point mutation Hepatoblastomas. Overexpression Hepatocellular carcinoma Immediate early response gene. Cyclin D2 is a target. Thousands of binding sites. Overexpression checkpoint bypass (GF+), apoptosis (GF-) Translocated from chromosome 8 in Burkitt lymphoma. Amplified in nueroblastoma On Chromosome 2 Amplified in small cell carcinoma of lung On chromosome 11. Binds CDK4 to phosphorylate RB, allowing G1 S phase transition. Translocated in Mantle Cell (11;14). Amplified in Breast, esophageal cancers. Complexes with CDK2. Expressed late G1. Allows G1S. Expression dependent on E2F family of TFs. Overexpression Breast Cancer. Forms complex with Cyclin D that phosphorylates RB. Amplification, point mutation melanomas, sarcoma, glioblastoma.
TUMOR SUPPRESSOR GENES .
Establishes stable cell-cell junction. 50% of tumors contain mutation. p53 is required for the G 1/S checkpoint and is a main component of the G2/M checkpoint. melanocytes. Can later develop malignant peripheral sheath tumors. Chromosome 17p13. APC downregulates b-catenin by ubiquitination. On cytoskeleton cytoskeltal stability. hypermethylation leads to inactivation. causes cell cycle arrest and apoptosis. Chromosome 17q21. Blocks CyclinD/CDK4 phosphorylatoin of RB. Tumor suppressor gene altered in the majority of cancers. Li Fraumani syndrome = 1 allele lost. stomach. HPV E6 degrades p53. Germline Mutation in 1 allele bilateral schwannomas. Loss key in EMT. increasing malignancy chance. Frequent in epithelial cancers. Fanconi anemia! BRCA1 plus pancreas. Connected to bCatenin and actin skeleton intracellularly. Phosphorylates R-SMAD SMAD 4 binding CDKI transcription. CDKI. Phosphatase and Tensin homologue.1. Receptor is serine-threonine kinase complex of I and II. Regulation of cell cycle. Involved in homologous recombination repair. Expression downreagulated by SNAIL. Member of SWH tumor suppressor pathway. Regulates mesenchymal to epithelial transition. thyroid. In adult’s overexpression can lead to tumorigenesis. Chromosome 18q21 Binds R-SMAD in TGF-b pathway CDKI expression. Normal function to inhibit signal transduction. Involved in gonadal and renal differentiation. Bcatenin +TCF upregulates cyclin D1 and c-MYC. Neurofibromin = GTPase –Activator Protein (GAP) Inner surface of PM. Located on 16 q. Retinoblastoma and osteosarcoma. Wilm’s tumor if inactivated. 83% of colon has mutation in TGF-b pathway. Breast and ovarian cancers. Second hit = Loss of heterozygosity (LOH). Membrane associated phosphatase on chromosome 10q23. Hypophosphorylated binds E2F. Signal by WNT stops APC. Phosphorylation by CyclinD/CDK4 leads to E2F release and p27. 100% of pancreatic. Mutation unregulated proliferation. prostate cancers. Crucial for induction of senescence. Child who inherits one mutant allele is “heterozygous” and normal. Homology with RBC cytoskeletal protein Band 4. Protein binds Binds E2F. p53 WT1 P16/INK4a BRCA1 BRCA2 . Mediate epithelial cell adhesion. stomach. HPV E7 will bind and release E2F proliferation. cholangiocarcinomas. 11p13. Acts mainly through p21 to cause cell cycle arrest.1 Most common genetic alteration in tumors. particularly breast. endometrial cancers. Produces Merlin. Germline Familial gastric cancers. Chromosome 5q21. Loss leads to easy disaggregation of cells metastatic spread. bile ducts. Mutation in type II colon. Chromosome 18q21 13q14 Regulation of cell cycle. Part of WNT pathway. Levels of p53 are negatively regulated by MDM2 through a feedback loop.TGF–b pathway TGF-b receptor E-cadherin NF1 NF2 APC/b-catenin PTEN SMAD2 SMAD4 RB1 TGF is potent inhibitor of proliferation. Thousands of polyps by 20. 25x increase in risk of cancer. Inhibitor of PI3K/AKT pathway (Prosurvival/growth path) TGF-b pathway. “Blocker” of cell progression from G1S. endometrium. Chromosome 13q12-13. neck tumors. Inhibition of RAS. Causes apoptosis by inducing the transcription of pro-apoptotic genes such as BAX. 70-80% of familial colon cancers implicated. Somatic mutation (reduced expression) carcinoma of stomach. head. One inherited mutant allele NFM1 (benign neurofibromas and optic gliomas after inactivation of 2nd allele). Mutation leads to sense of loss of contact. Involved in homologous recombination repair. In cervical cancer. Subject to methylation. Mutated in Cowden syndrome (AD disorder with frequent benign tumors of skin appendages). Mutation pancreatic cancers. Bladder. ALL.
Involved in homologous recombination repair. leading to cytochrome C escape and APAF1 activation caspase 9 activation. p53 is required for the G 1/S checkpoint and is a main component of the G2/M checkpoint. 25x increase in risk of cancer. Phosphorylate p53 to pause cell cycle. 18) Roughly 10-20% of DLBCL. Inhibited by BCL2. Causes apoptosis by inducing the transcription of pro-apoptotic genes such as BAX. bile ducts. Caspase 3 is most important executioner. directly promote mitochondrial permeabilization. Caspase 9 active in intrinsic pathway with Cytochrome C. which attracts procaspase 8 caspase 3 activation (executioner caspase) and DNA cleavage. Involved in homologous recombination repair. Chromosome 17q21.1 Most common genetic alteration in tumors. Follicular lymphoma t(14. 3p21. 30%. causes cell cycle arrest and apoptosis. Acts mainly through p21 to cause cell cycle arrest. . Under regulation of p53. 30% Ataxia telangiectasia mutated. Breast and ovarian cancers. which attract FADD. Barrier to mitochondrial permeabilization. Subject to methylation. Caspase 8 active in extrinsic pathway with CD95/Fas. Chromosome 18q21. Chromosome 17p13. Reduced levels antiapoptosis. Fanconi anemia! BRCA1 plus pancreas. prostate cancers. stomach. BAX BCL2 Caspases p53 DNA REPAIR GENES MSH2 MLHI ATM BRCA1 BRCA2 Chromosome 2p16 Involved in HNPCC. HPV E6 degrades p53. melanocytes. Lead to DNA cleavage and cell death. Tumor suppressor gene altered in the majority of cancers. Germ line mutation. Involved in HNPCC. 50% of tumors contain mutation. Anti-apoptotic.MOLECULES THAT PARTICIPATE IN APOPTOSIS CD95/Fas Extrinsic death receptor pathway. Apoptosis regulators. Chromosome 13q12-13. Silenced by epigenetic modification in prostate cancers. Activation by FasL leads to trimerization of receptor and cytoplasmic death domains. Can’t repair DNA damage when ATM is damaged by ionizing radiation. Along with BAK. Li Fraumani syndrome = 1 allele lost. Levels of p53 are negatively regulated by MDM2 through a feedback loop.
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