Chapt. 18 Cancer Molecular Biology of Cancer Student 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 tumorsuppressor genes leads to cancer P53, Rb, regulators of Ras Karyotype analysis can reveal translocation Karyotype analysis reveals transloction of chromosome 22 to 9 in CML chronic myelogenous leukemia has fusion protein Bcr-Abl Fig. 18.1 Cancers involve sequential mutations Cancer involves sequential accumulation of mutations in genes involved in normal cell growth and differentiation: cancer cells do not Fig. 18.1 respond to normal constraints cancer cells are immortal increasing abnormalities, lack attachment Can inherit one bad gene Damage to DNA can lead to mutaitons A. 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) Fig. 18.2 nitrosoamine causes GC -> AT mutations 1
B. Gain-of-function mutations in Proto-ongogenes Proto-oncogenes have normal roles for cell growth, proliferation: Mutate to Oncogenes Mutate so function better. in absence of normal activating signals: Overexpress Hyperactive protein Fusion protein Controlled by other promoter (inappropriate) Fig. 18.3 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 enzymes Table 1 examples of oncogenes Classes of oncogenes gene mechanism Growth factor platelet-derived growth factor sis overexpression Growth factor receptor platelet-derived gf receptor PDGFR translocation Signal transduction G-proteins Ras point mutation tyr kinase abl translocation Hormone receptors retinoid receptor RARa translocation Transcription factors Myc amplification Cell-cycle regulators cyclins cyclin D amplification cyclin-dependent kinase CDK4 point mutation Oncogenes and signal transduction pathways Growth factor signaling pathways provide sites for proto-oncogene transforming mutations: Only need to mutate one allele (one gene) Dominant effect See Table 1 Fig. 18.4 2
Signal transduction proteins and phosphorylation cascade Phosphorylation 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 proliferation Fig. 18.5 Oncogenes and the Cell cycle Cyclins 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 G 1 -> S transition is critical Commits to replication Responds to hormones G 2 -> M spindle check Fig. 18.6 Cyclin-CDK Cyclins are synthesized, function to bind CDK, and degraded CKIs are cyclin-dependent kinase inhibitors CDKs are also regulated: activated by PO 4 (by CAK cyclinactivating kinases) inhibited by additional PO 4 Oncogenes include: Overactive cyclins, mutant cdks Fig. 18.7 Control of G1/S transition in cell cycle: Fig. 18.8 Control of G1/S is critical: regulation of E2F by Rb, CDK, cyclin CKI include p21, p16 (INK) 3
IV. Tumor-suppressor genes Tumor-suppressor genes encode proteins that inhibit cell proliferation: mutate both copies Table 18.2 class protein location Adhesion protein E-cadherin cell surface Signal transduction NF-1 under membrane Transcription factor cell-cycle regulator p16 (INK4) nucleus Rb nucleus A. Some tumor suppressors regulate cell cycle directly Retinoblastoma (Rb) protein binds E2F, prevents transcription and G1/S until signal:(fig. 18.8) Mutate both copies Cell loses control Hereditary cancer tendency Fig. 18.9 Cell cycle/ apoptosis p53 nucleus DNA repair BRCA1 nucleus Phosphorylation controls transition G1 to S: cycd-cdk inactivates Rb ->E2F activates transcription Phosphorylation controls transition G1 to S: E2F activated transcription: cyclins A, E and Cdk2 activate prereplication complexes Genetics 15.12A Genetics Fig 15.12 B 4
P53 is guardian of genome P53 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 repair Some tumor suppressors affect receptors, signal transduction 1. 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 neurofibromatosis Fig. 18.10 Fig. 18.11 2. Tumor suppressors and proto-oncogenes Tumor 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 active Fig. 18.12 Tumor suppressor genes can affect cell adhesion Tumor cells metastasize, lose cell adhesion: Normal adhesion from cadherins, link cytoskeleton Mutated cadherins promote cell migration β-catenin also transcription factor; Bound by inhibitor APC APC is tumor suppressor Fig. 18.13 5
Cancer involves sequential mutations Cancer involves sequential mutations that increase aberrant cell activity: 2-hit model: mutations in at least two different types of genes (tumor suppressor, oncogene) Cancer is many different diseases Cancer is many different diseases at the molecular level: not all colon cancers have same defect defects in particular signaling pathways can cause cancers in different tissues (also lack of apoptosis) Fig. 18.18 Fig. 18.19 Viruses can also cause cancer RNA retroviruses: HTLV-1 adult T cell luekemia HIV immunosuppression non-hodgkins lymphoma Hepatitis C liver DNA viruses: HPV: cervical cancer Epstein Barr (a herpesvirus) interfere apoptosis Review questions 2. The mechanism through which Ras becomes an oncogenic protein is which of the following? A. Ras remains bound to GAP B. Ras can no longer bind camp C. Ras has lost its GTPase activity D. Ras can no longer bind GTP E. Ras can no longer be phosphorylated by MAP kinase 6