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Cell transformation Mechanisms of effect of oncogenes and tumor suppressor genes Plan of seminar • A short introduction to the topic • Oncogenes/Protooncogenes/Oncosupress ors • Viruses and tumors • The easy task Cell transformation Metamorphosis of a normal cell to cancer cell • It is irreversibile • Gradual/multistep Comparision of a normal and a cancer cell Normal cell • A limited potential to dividing • A contact inhibition • Great dependence on other cells !!! A cancer cells does not divide more quickly than a normal cell, but continually !!! Cancer cell • An immortality (see HeLa cells) • A loss of contact inhibition • An independence on surrounding • A changes in surfaces molecules and chromosomes • A resistance to apoptosis Tumor • Benign - a solid structure, formed by cancer cells and normal cells (stroma), in principle compact localization, can be removed • Malignant - spreading of cancer cells to body (metastasis), mostly beginning of cancer DNA modifications - mutations • Induced mutations (induced by mutagenes), spontaneus mutations • There is a relationship between mutations and cell transfromation • The types of mutations • The sources of mutations - mutagenes Mutagenes • Physical: UV radiation, X rays, gama radiation (leukaemia, skin cancer) • Chemical: Substances interacting with DNA, capable of mutate this • Biological: viruses, other parasites (cervical cancer, hepatocelular carcinoma) Protooncogene/Oncogene Protooncogene - original protein Oncogene - altered protein Oncoproteins/Oncosupresors Oncoprotein - protein with altered function or level of expression inducing cell transformation. The heredity is dominant one chanched allele can cause transformation in all daughter cells. Onkosupressor = antioncogene - protein, that prevents transformation. The heredity is recesive - both alleles has to be damaged not to protect the daughter cells against transformation. The point mutation of Ras can cause its continuous activation Point mutatin in the GTPcleavage domain. GTP can not be cleaved - it is continuously activated Loss of extracellular regulatory domains causes continuous activation of receptor tyrosine kinases Moreover, some aminoacids can be phosphorylated and it leads to inhibition of the protein. If the aa is mutated, oncogen is created. Signaling pathways and proteins, that can be altered Ras protein Src protein MAPKK Myc, Fos Jun Raf protein Receptor kinases Growth factors P53, pRb Bcl-2 Groove factors: v-sis: c-sis = gene for B chain of PDGF v-hst-1: c-hst = gene for FGF-4 autocrine stimulation Receptor tyrosinkinases: v-erbB: c-erb = EGFR gene erhytroblasts, fibroblasts, v-fms:c-fms = M-CSFR gene met: c-met = HGFR gene trkA: c-trkA = NGFR gene Serin-threoninkinases: v-Raf: c-Raf gene Non receptor tyrosinkinases: v-abl: c-abl, v-src: c-src, v-mos: c-mos G proteins: v-Hras: c-Hras, v-Kras: c-Kras N-ras: c-Nras Transcription factors: v-fos: c-fos v-myc: c-myc v-myb: c-myb v-jun: c-jun The list of protooncogenes from previous slide 12 Tumor supressor genes (antioncogenes) • p53 gene • pRb gene • genes for proteins involved in DNA reparation 13 pRb Rb is fosforylated by complex of G1 cdk/cyclin. Subsequently it is released from E2F protein. E2F then induces a expression of S - phase proteins. Mutations of Rb lead to continual activation of E2F. p53 Human Li-Fraumeni Syndrome (rare inherited cancer; heterozygous p53 mutation) p53 blocks a cell cycle at G1 phase (by production of p21). Impaired DNA can be repaired. If the damage is to serious and there is no possibility to repair it, p53 induce production of Bax protein and it activates a mitochondrial pathway of apoptosis. Viruses and tumors 16 HCV • Chronical persistent infection observed in adult immunocompetent patient (70 – 85% pacientů) it can lead to hepatocelular carcinoma by the same mechanisms like HBV • Transmission: by blood - nonsterile injection needles, blood transfusion, drug users, sexual? • Treatment: Interferon a, ribavirin (20 - 30%, toxic) • 130 000 000 HCV positive persons: 0,1% (UK) - 20% (Egypt) Pakistan (4.8%) and China (3.2%), more than 350 000 people die from HCV-related liver diseases each year • Vakcinace: there is no vaccination • Prevention: control of blood and blood derivates, disposable sterile needles Hepadnaviruses • In 20% cases hepatitis B goes to chronical phase • The hepatocelular carcinoma can be developed in decades • The development of tumor is associated with abnormal loss of hepatocytes in 95% of cases. They are removed by immune system due to infection by the virus. • The damaged liver tissue recover and so permanently proliferating hepatocytes gain mutations that lead to cell transformation. • There are 350 mil. HBV infected worldwide • Transmission by blood, throught injections (drugs, tatoo, hospitals) and sexual • There is commonly used hexavaccine or combined vaccines against HBV nad HAV Papilomaviruses • More than 100 species (about 40 was sexual transfer described, cca 15 have oncogenical potential) • Strongly species - specific, infection of skin and mucous membrane where can induce formation of tumors • Most common sexual transmitted infection (to 80% humans infected during the life) • Most common cause of world-wide incidence of cervical carcinoma are HPV types 16 (53-70 %) and 18 (13-26 %) • Cervical carcinoma is caused by HPV 16 a 18 in approximately 0,1% infected women • World-wide 500,000 new cases a year, 275,000 humans die a year. Usually suppressed by immune system, no tumor is formed, chronical infections are high risk, e. g. Viral genom can be integrated • Typical cancer cells produced E6 and E7 Oncogenes of papilomaviruses Protein E6 –degradation p53 –interaction with Bak (inhibition of apoptosis) – activation of telomerases Protein E7 –Inhibition of Rb protein –Inactivation of p21Cip and p27Kip A) Viral oncogenes, that have no model in infected cells Herpesviruses Epstein-Barr virus - HHV4 (EBV) – Burkitt ´s lymfom – South - east Africa - EBV + other factors - malaria, imunosupression etc – Very often there is translocation of gene of primary response – gene, myc, next to the gene for antibodies. In result, fused gene is created and deregulation of cell signallization follows – Moreover, herpesviruses are infectious agents causing nasofaryngal carcinoma, Kaposi ´sarkoma and and others infectious diseases B) Herpesviral oncogenes – oncogenes, that have model gene in cell proteins, they were incorporated into the viral genom many thousands years ago Cyclin/CKI pathways vCYC X RB p53 X LANA vIL-6 vIRF c-myc X X v Bcl-2 vFLIP Control of Cell Cycle Progression Induction of Apoptosis Antman & Chang. N. Engl. J. Med. 342:1027, 2000. Retroviruses and tumors • C) Viral oncogenes of acute oncoviruses - cellular protooncogenes, that are incorporated into viral genom de novo during infection, this deactivates the virus, they do not cause any know disease • Retroviruses can incorporated into cellular genom (it is the same in 5% in hepatocallular carcionma induced by hepadnaviruses), cellular protooncogene is then expressed from viral promotor deregulation, very rare • Tumors can be also induced by protein Tax (viral oncogene without cellular template) of virus HTLV-1 Japan 10% infected, Jews in Ethiopia, 0,1% leucemia, very long incubation period - to 35 years, HTLV - 1, HTLV -2, transmission like HIV virus, 15 –25 milionů infict. HTLV -1 Task Classify the terms in bold from this presentation into following groups: Oncogenes Oncosupressors Protooncogenes The others