Chapt. 18 CancerKaryotype analysis can reveal translocationCancers involve sequential mutationsDamage to DNA can lead to mutaitonsB. Gain-of-function mutations in Proto-ongogenesMutations in DNA repair enzymes can cause cancer:Table 1 examples of oncogenesOncogenes and signal transduction pathwaysSignal transduction proteins and phosphorylation cascadeOncogenes and the Cell cycleCyclin-CDKControl of G1/S transition in cell cycle:IV. Tumor-suppressor genesA. Some tumor suppressors regulate cell cycle directlyPhosphorylation controls transition G1 to S: cycD-Cdk inactivates Rb ->E2F activates transcriptionPhosphorylation controls transition G1 to S: E2F activated transcription: cyclins A, E and Cdk2 activate prereplication complexesP53 is guardian of genomeSome tumor suppressors affect receptors, signal transduction2. Tumor suppressors and proto-oncogenesTumor suppressor genes can affect cell adhesionCancer involves sequential mutationsCancer is many different diseasesViruses can also cause cancerReview questionsChapt. 18 CancerMolecular Biology of CancerStudent Learning Outcomes:• Describe cancer – diseases in which cells no longer respond• Describe how cancers come from genomic mutations (inherited or somatic)• Explain how some gain of function mutations in proto-oncogenes cause oncogenes•Growth factors, receptors, Ras, cyclins• Explain how loss of function of tumor-suppressor genes leads to cancer•P53, Rb, regulators of RasKaryotype analysis can reveal translocation Karyotype analysis reveals transloction of chromosome 22 to 9 in CML• chronic myelogenous leukemia has fusion protein Bcr-AblFig. 18.1Cancers involve sequential mutationsFig. 18.1Cancer involves sequential accumulation of mutations in genes involved in normal cell growth and differentiation:• cancer cells do not respond to normal constraints• cancer cells are immortal• increasing abnormalities, lack attachment•Can inherit one bad geneDamage to DNA can lead to mutaitonsFig. 18.2 nitrosoamine causes GC -> AT mutationsA. Chemical and physical agents can damage DNA:• Break DNA chains• Cause translocations• Modify bases • DNA damage can be repaired; mutations if not repaired• Carcinogens are mutagens• (see chapter 13)B. Gain-of-function mutations in Proto-ongogenesFig. 18.3Proto-oncogenes have normal roles for cell growth, proliferation: Mutate to Oncogenes•Mutate so function better.in absence of normalactivating signals:•Overexpress•Hyperactive protein•Fusion protein•Controlled by other promoter (inappropriate)Mutations in DNA repair enzymes can cause cancer:Mutations in DNA repair enzymes can cause cancer:•DNA repair enzymes can correct damage•They are tumor-suppressor genes (need to mutate both)•Breast cancer linked to Brca1, Brca2 mutations•Xeroderma pigmentosum to excision repair•HNPCC (hereditary nonpolyposis colorectal cancer) linked to mutations in mismatch repair enzymesTable 1 examples of oncogenesClasses of oncogenes gene mechanismGrowth factor platelet-derived growth factor sis overexpressionGrowth factor receptor platelet-derived gf receptor PDGFR translocationSignal transduction G-proteinsRas point mutation tyr kinase abl translocationHormone receptors retinoid receptor RARa translocationTranscription factors Myc amplificationCell-cycle regulatorscyclins cyclin D amplificationcyclin-dependent kinase CDK4 point mutationOncogenes and signal transduction pathwaysGrowth factor signaling pathways provide sites for proto-oncogene transforming mutations:•Only need to mutate one allele (one gene)Dominant effect•See Table 1Fig. 18.4Signal transduction proteins and phosphorylation cascadeFig. 18.5Phosphorylation cascade from activated Ras (Ras-GTP)•Ras activates ser/thr kinase Raf•Raf is a MAPKKK (mitogen-activated protein Kinase kinase kinase)• Raf activates MEK•(a MAPKK)• MEK activates MAP kinase• MAP kinase phosphorylates many proteins •Transcription factors can mutate to oncogenes•Mutations that keep proteins active cause cell proliferationOncogenes and the Cell cycleFig. 18.6Cyclins and cyclin-dependent kinases (CDK) control passage through cell cycle:•Different cyclins and CDKs control different points•Cyclins transient; cdks persist•Go is quiescent cell•G1 -> S transition is critical•Commits to replication• Responds to hormones•G2 -> M spindle checkCyclin-CDKCyclins are synthesized, function to bind CDK, and degradedCKIs are cyclin-dependent kinase inhibitorsCDKs are also regulated:• activated by PO4 (by CAK cyclin-activating kinases)• inhibited by additional PO4Oncogenes include:• Overactive cyclins, mutant cdksFig. 18.7Control of G1/S transition in cell cycle:Fig. 18.8Control of G1/S is critical:regulation of E2F by Rb, CDK, cyclin CKI include p21, p16 (INK)IV. Tumor-suppressor genesTumor-suppressor genes encode proteins that inhibit cell proliferation: mutate both copiesTable 18.2 class protein locationAdhesion protein E-cadherin cell surfaceSignal transduction NF-1 under membraneTranscription factorcell-cycle regulator p16 (INK4) nucleusRb nucleusCell cycle/ apoptosis p53 nucleusDNA repair BRCA1 nucleusA. Some tumor suppressors regulate cell cycle directlyRetinoblastoma (Rb) protein binds E2F, prevents transcription and G1/S until signal:(Fig. 18.8)•Mutate both copies•Cell loses control•Hereditary cancer tendencyFig. 18.9Phosphorylation controls transition G1 to S: cycD-Cdk inactivates Rb ->E2F activates transcriptionGenetics 15.12APhosphorylation controls transition G1 to S:E2F activated transcription:cyclins A, E and Cdk2 activate prereplication complexes Genetics Fig 15.12 BP53 is guardian of genomeP53 responds to DNA damage: stops cell cycle to permit repair (or cell suicide – apoptosis)•P53 mutated in 50% of tumors•Induction of p21 stops cyclin-CDK•Induction of GADD stops replicaiton, permits repairFig. 18.10Some tumor suppressors affect receptors, signal transductionFig. 18.111. Regulators of Ras are tumor suppressors:•GAP proteins (GTPase) bind active Ras, stop signal•NF-1 (neurofibromin) is GAP for RAS in neuronal tissue•Mutated NF-1 give neurofibromatosis2. Tumor suppressors and proto-oncogenesTumor suppressors and proto-oncogenes in path:•Patched inhibits Smoothened, coreceptor•HH ligand binding releases inhibition, activating signal•S is proto-oncogene; mutation can keep active•P is tumor suppressor; mutations ruining keep S activeFig. 18.12Tumor