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Cell transformation Mechanisms of effect of oncogenes and tumor suppressor genes (n.130) Plan of seminary • A short repeating of 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 Cancer cell • An immortality • A loss of contact inhibition • A contact inhibition • An independence on surrounding • Great dependence on other cells • A changes in surfaces molecules and chromosomes !!! A cancer cells does not divide more quickly than a normal cell, but continually !!! • A resistance to apoptosis Tumor • Benign – a solid structure, formed by cancer cells and normal cells stroma), in principle clear localization, can be removed • Malignant – spreading of cancer cells to body (metastasis), mostly beginning of cancer Types of tumors • Carcinomes 85% epitheliums Sarkomas 2% connectivum tissues Lymfomas 5% spleen, nods Leukemias leukocytes 3% 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 • Physical: UV radiation, X rays, gama radiation (leukaemia, skin cancer) • Chemical: Substances interacting with DNA, able to mutate this • Biological: viruses, other parasites (cervix, hepatocarcinom) Protooncogene/Oncogene Protooncogene – original protein Oncogene – altered protein Oncogenes/Oncosupresors Oncogene – protein with altered function or level of expression. It´s dominant - one chanched allele can caused transformation Onkosupressor = antioncogene – protein, that prevents transformation. It´s recesive – both alleles has to be damaged. The point mutation of Ras can cause its continuous activation Point mutatin in the binding domain for GTP. It can not be cleaved – it´s continuously activated Loss of extracellular regulatory domains causes continuous activation of receptor tyrosine kinases Some aminoacids can be phosphorylated and it leads to inhibition of the protein. If the aa is mutated, oncogen is created Signalling 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 hst-1: gene for FGF-4 autocrine stimulation Receptor tyrosinkinases: v-erbB = EGFR gene erhytroblasts, fibroblasts, v-fms: = M-CSFR gene met: HGFR gene trkA: NGFR gene Serin-threoninkinases: Raf gene Non receptor tyrosinkinases: v-abl: gene for non receptor tyrosinkinases Abl v-src, v-mos G proteins: v-Hras, v-Kras, Nras Transcription factors: v-fos, v-myc v-myb v-jun 13 Tumor supressor genes (antioncogenes) • p53 gene • pRb gene • proteins involved in DNA reparation 14 Rb Rb is fosforylated by complex of G1 cdk/cyclin. After that 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 17 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 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. 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 aothers 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 induced by protein Tax (viral oncogene without cellular template) of virus HTLV-1, too Japan 10% infected, 0,1% leucemia, very long incubation period – to 35 years Task Classify the terms in bold from this presentation into following groups: Oncogenes Oncosupressors Protooncogenes The others