New Material DNA Replica on Cell Cycle Cancer Cancer Ras Activation by Point Mutation Ras Activation by Point Mutation Ras was also discovered as an oncogene in humor tumors by gene transfer Ras was discovered as an oncogene in a retrovirus Mutations that activate Ras are at amino acids 12 59 and 61 Ras was discovered as an oncogene in a retrovirus These positions contact the phosphate of the GTP Activated Ras mutants have decreased GTPase Ras was also discovered as an oncogene in humor tumors by gene transfer Mutations that activate Ras are at amino acids 12 59 and 61 Ras Oncogene Ac0va0on via These positions contact the phosphate of the GTP Point Muta0on Activated Ras mutants have decreased GTPase Cannot turn self off so signal continues Oncogene activation results from mutation of specific sites in specific proteins discovered as oncogene in a Ras ac va on retrovirus also discovered as oncogene in human tumors via gene transfer Cannot turn self off so signal continues Oncogene activation results from mutation of specific sites in specific proteins muta ons that ac vate Ras located AA 12 59 61 these posi ons contact phosphate of GTP ac vated Ras mutants have decreased GTPase thus cannot turn self o signal con nues gives too much growth signal oncogene ac va on results from muta on of speci c sites in speci c proteins ac ve Ras MAP K cascade Mul0ple Muta0ons Work Synergis0cally Multiple Mutations Work Synergistically Coopera0on of Oncogenes Cooperation of Oncogenes Theory coopera on of oncogenes mul ple Cooperation of oncogenes oncogenes work together Multiple Hit Theory supports Mul0ple Hit Combination of ras plus myc induces more tumors in mice combo of Ras Myc Still takes other events to initiate induces more tumors in tumor cell line to form as tumors mice originate from single cells and are not present from birth other events s ll required to ini ate tumor cell line to form since tumors originate from single cells are not present birth Oncogenes Examples normal growth factor roles but too much of a good thing is a bad thing PDGF EGF EGFR growth factors growth factor receptors cytoplasmic tyrosine kinases SRC Abl GTP binding proteins S T kinases transcrip on factors CDKs cyclins Ras heterotrimeric G proteins RAF MEK MAP KK Akt Myc Fos Jun cyclin D1 CDK4 Tumor Suppressor Genes Tumor Suppressor Genes Retinoblastoma Rb Families with one copy mutant have high incidence of cancer RB re noblastoma families w 1 mutant copy have high incidence of cancer p53 Tumor Suppressor Gene p53 Tumor Suppressor Gene Involved in DNA Damage Checkpoint Transcription Factor Can Arrest Cell Cycle P53 mutations present in 50 of all human tumors Many of the other 50 of tumors have mutations in involved in DNA damage checkpoint transcrip on factor can arrest cell cycle p53 associated proteins such as Mdm2 If continue growth wit DNA damage more damage In normal cells if damage cannot be repaired p53 have muta ons in p53 induced apoptosis associated w proteins like Mdm2 p53 muta ons present in 50 of all human tumors many of other 50 of tumors Cancer cell escapes apoptosis since p53 is deficient con nue growth w DNA damage more damage if damage can t be repaired in normal cells p53 induced apoptosis cancer cell escapes apoptosis since p53 de cient p53 Tumor Suppressor Gene Involved in DNA Damage Checkpoint Transcription Factor Can Arrest Cell Cycle P53 mutations present in 50 of all human tumors Many of the other 50 of tumors have mutations in p53 associated proteins such as Mdm2 If continue growth wit DNA damage more damage In normal cells if damage cannot be repaired p53 induced apoptosis Cancer cell escapes apoptosis since p53 is deficient break 1 fuse break 2 w o p53 to arrest cell cycle or cause apoptosis con nued growth will cause more damage Loss of p53 Promotes Cancer Growth in 2 Ways p53 Tumor Suppressor Gene 1 cannot stop cell cycle to Involved in DNA Damage Checkpoint Transcription Factor Can Arrest Cell Cycle P53 mutations present in 50 of all human tumors Many of the other 50 of tumors have mutations in repair DNA p53 associated proteins such as Mdm2 loss of p53 causes DNA If continue growth wit DNA damage more damage damage no cell cycle In normal cells if damage cannot be repaired p53 induced apoptosis arrest for repair Loss of p53 Promotes Cancer Growth 2 Ways cannot stop cell cycle to repair DNA cannot initiate p53 dependent apoptosis Cancer cell escapes apoptosis since p53 is deficient 2 cannot ini ate Loss of p53 causes DNA damage No cell cycle arrest for repair p53 dependent apoptosis no p53 induced apoptosis to No p53 induced apoptosis to kill tumor cell kill tumor cell Tumor cells with mutant p53 are more tumor cells w mutant p53 sensitive to DNA damage induced by radiation or drugs Tumor cells more sensi ve to DNA damage induced by radia on or drugs escape drugs with MDR Also See Figure 20 40 tumor cells escape drugs w MDR about p53 DNA Tumor Virus Drive Cell Into S phase Adenovirus takes over the cell so virus can replicate DNA DNA Tumor Virus Drives Cell into S Phase Adenovirus E6 binds p53 and E7 binds RB No cell cycle arrest or apoptosis induced by p53 so wild type virus can replicate its DNA and cell grows too Cancer cells lack p53 adenovirus takes over cell so virus can replicate DNA adenovirus E6 binds p53 No cell cycle arrest and no p53 dependent apoptosis E7 binds RB no cell cycle arrest or apoptosis induced by p53 WT virus can replicate its DNA cell grows cancer cells lack p53 no cell cycle arrest no p53 dependent apoptosis Tumor Suppressor Genes Overview RB p53 PTEN loss of func on causes over ac va on of PKB phosphatase that removes C3 from phospha dyl inositol REVERSES ac on of PIH3K BLOCKS ac va on of PKB Akt PKB ini ally known as oncogene Akt CKI loss of func on causes inappropriate start of cell cycle nega ve regulator of S phase entry BLOCKS CDKs BRCA1 BRCA2 breast cancer gene families w 1 bad copy have high incidence of breast cancer involved in DNA repair Adenomatous Polyposis Cell APC colon cancer controls catenin in WNT signaling pathway if APC is absent excess stem cell prolifera on Oncogenes Tumor Suppressor Oncogenes and Tumor Suppressor Genes are Found in the Same Pathways Genes Found in Same Pathways RTK MAP K Pathway Full of CancerHRelated Genes The RTK MAPK Pathway is Full of Cancer Related Genes EGF EGF receptor EGF Ras EGF Receptor RAS RAF RAF MEK MEK MAPK MAP K C fos CHFos C jun AKT CHJun PI 3K Akt PTEN PIH3K PTEN Sequen0al Mul0ple Muta0ons Lead to