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 A contact inhibition Great dependence on other cells Cancer cell An immortality A loss of contact inhibition An independence on surrounding A changes in surfaces molecules and chromosomes A resistance to apoptosis !!! A cancer cells does not divide more quickly than a normal cell, but continually !!!

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 Carcinomes85% epitheliums Sarkomas 2% connectivum tissues Lymfomas 5% spleen, nods Leukemias 3% leukocytes

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 proteinOncogene – 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 Growth factors Receptor kinases Src protein Ras protein Raf protein MAPKK Myc, Fos Jun 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 13 Non receptor tyrosinkinases: v-abl: gene for non receptor tyrosinkinases Abl v-src, v-mos G proteins: v-Hras, v-Kras, Nras Serin-threoninkinases: Raf gene Transcription factors: v-fos, v-myc v-myb v-jun

Tumor supressor genes (antioncogenes) 14 p53 gene pRb gene proteins involved in DNA reparation

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 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. Human Li-Fraumeni Syndrome (rare inherited cancer; heterozygous p53 mutation) p53

17 Viruses and tumors

Protein E6 –degradation p53 –interaction with Bak (inhibition of apoptosis) – activation of telomerases Protein E7 –Inhibition of Rb protein –Inactivation of p21 Cip and p27 Kip Papilomaviruses 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

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 Retroviruses and tumors

Task Classify the terms in bold from this presentation into following groups: Oncogenes Oncosupressors Protooncogenes The others