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Tumor Viruses Viruses can cause benign tumor or malignant tumors in many species of animals . Only a few viruses are associated with human tumors. Tumor viruses has no characteristic size , shape , or chemical composition . Some are large ,and some are small ; some are enveloped, and others are naked ; some have DNA as their genetic material , and others have RNA .The factor that unites all of them is A ***Role of Tumor Viruses in Malignant Transformation Malignant transformation is a permanent change in the behavior of the cell. The use of temperature –sensitive mutant of rouse sarcoma virus which has an altered transforming gene that is functional at the low, permissive temperature (35ºc) but not at the high, restrictive temperature( 39ºc). When chicken cell were infected at35ºc they transformed as expected , but when incubated at 39ºc they regained their normal morphology and behavior within few hours . Days or weeks later , when these cells were returned to 35ºc they recovered their transformed phenotype, thus continued production of some functional virus - encoded protein is required for the transformed state. Provirus and Oncogenes Viral tumor genesis occurs are expressed in the terms provirus and oncogene. 1- In the provirus model the genes inter the cell at the time of infection by tumor virus. 2- In the oncogene model, the gene for malignancy are already present in all cells of the body by virtue of being present in the initial sperm and egg. These oncogenes encoded proteins that encourage cell growth , example fibroblast growth factor . In oncogene model , carcinogen such as chemicals , radiation, and tumor viruses activate cellular oncogenes to overproduce these growth factors. This initiates inappropriate cell growth and malignant transformation . ****Evidence for the provirus mode consist of finding copies of viral DNA integrated in cell DNA only in cell that have been infected with the tumor virus . The corresponding uninfected cell have no copies of the viral DNA. The first direct evidence that oncogenes exist in normal cell was based on results of experiments in which the DNA copy of the onc-gene of the chicken retroviruses , rouse sarcoma virus was used as a probe DNA in normal embryonic cell hybridized to the probe indicating that the cells contain a , gene homologous to the viral gene . It is hypothesized that cellular oncogenes ( proto-oncogenes) may be the3 precursor of viral oncogenes. ****Although cellular oncogenes and viral oncogenes are similar they are not identical .They differ in base sequence at various points and cellular oncogenes have exons and introns, where as viral oncogenes do not have. */* It seems likely that viral oncogen were acquired by incorporation of cellular oncogenes into retrovirus lacking these gene . Retroviruses can be though of as transducing agents , carrying oncogenes from one cell to another . ### A marked diversity of viral oncogene function has been found …..some encode a protein kinase that specifically phosphorylates the amino acid tyrosine . The cellular protein(s) phosphorylated by this kinase are unknown in contras to the commonly found protein kinase of cells, which preferentially phosphorylate serine. @@@ Other oncogenes have a base sequence almost identical to that of the gene for certain cellular growth factors. Several proteins encoded by oncogenes have their effect at the cell membrane (e.g., the ras oncogen encode a G protein ) ,where as some act in the nucleus by binding to DNA ( e.g., the myc oncogene encodes a transcription factor ). These observation suggest that growth control is a multistep process and that carcinogenesis can be induced by affecting one or more of several steps. 1- on the basis of the known categories of oncogenes the following model of growth control can be constructed after a growth factor binds to its receptor on the cell membrane , membrane –associated G – proteins and tyrosine kinases are activated . These, in turn , interact with cytoplasmic proteins or produce second messengers, which are transported to the nucleus and interact with nucleus factors ----DNA synthesis is activated , and cell division occurs . ****#### Over production or inappropriate expression of any of the above factors in bold face type can result in malignant transformation +++++ Not all tumor viruses of the retrovirus family contain onc genes How do these viruses cause malignant transformation ?. It appear that the DNA copy of the viral RNA integrates near a cellular oncogenes , causing a marked increase in its expression --------,overexpression of the cellular oncogenes may play a key role in malignant transformation by these viruses. Although it has been demonstrated that viral oncogenes can cause malignant transformation , it has not been directly shown that cellular oncogenes can do so. However the following incidence suggest that they do: 1-DNA containing cellular oncogen isolated from certain tumor cells can transform normal cells in culture .When the base sequence of these transforming cellular oncogenes was analyzed , it was found to have a single base change from the normal cellular oncogenes, i.e., it had mutated . In several tumor isolates , the altered sites in the gene are the same. 2-In certain tumors ,characteristic transformations of chromosomal segment can be seen. In Burkitt′s lymphoma cells, a translocation occurs that moves a cellular oncogenes ( c-myc ) from its normal site on chromosome 8 to a new site adjacent to an immunoglobulin heavy chain gene on chromosome 14 This shift enhances expression of the c-myc gene. 3- Some tumors have multiple copies of the cellularoncogenes, either on the same chromosome or on multiple tiny chromosomes . The amplification of these genes result in over expression of their m RNA and proteins. 4-Insertion of the DNA copy of the retroviral RNA (Proviral DNA) near a cellular oncogene stimulate expression of the c-onc gene. 5- Certain cellular oncogenes isolated from normal cell can cause malignant transformation if they have been modified to be overexpressed within the recipient cell. Sumry In summery, two different mechanisms, mutation and increased expression …..appear to be able to activate the quiescent ((protooncogene)) into a functioning oncogene capabile of transforming a cell. Cellular oncogene provide a rational for a carcinogenesis by chemical and radiation , example ,a chemical carcenogene might act by enhancing the expression of of cellular oncogene . Furthermore , DNA isolated from cell treated with a chemical carcenogene can malignant transform other normal cell . The resulting tumor cell contain cellular oncogenes from the chemically treated cell, and these genes are expressed with high efficiency. There is another mechanism of carcinogenesis involving celluler genes , namely, mutation of a tumor suppressor gene .A well documented example is the retinoblastoma susceptibility gene which normally acts as a suppressor of retinoblastoma formation when both alleles of this anti- oncogene are mutated ( made functional)--retinoblastoma occurs. Human papilloma virus and SV40 virus produce a protein that bind the protein induce by the retinoblastoma gene. Human papilloma virus also produces a protein that inactivates the protein encoded by the protein P53 gene , another tumor suppressor gene in human cells. The P53 gene encodes a transcription factor that activates the synthesis of a second protein which blocks the cyclindependent kinases required for the cell division to occur . The P53 protein also promotes apoptosis of cell that have sustained DNA damage or contain activated cellular oncogen . Apoptosis – educed death of these cells has a tumor –suppressive effect by killing those cells distained to become cancerous. Inactivation of tumor suppressor genes appears likely to be an important general mechanism of viral oncogenesis. Tumor suppressor genes are involved in the formation of other cancers as well, example , brest and colon carcinoma and varcomas. For example , in many colon carcinomas , two genes are involved and inactivated, the P53 gene and the DCC (deleted in colon carcinoma) gene. More than half of human cancers have a mutated P53 gene in the DNA of malignant cells. Evidence For Human Tumor Viruses. At present , only two viruses , Human T-cell lymphotropic virus and Human papilloma virus , are considered to be human tumor viruses. However, several other candidate viruses are implicated by epidemiologic correlation , by serologic relationship , or by recovery of the virus from tumor cell. Human T-cell lymphotropic virus : There are tow Human T-cell Lymphotropic virus (HTLV)isolated so far , HTLV-1 and HTLV-2 both of which are associated with leukemias and lymphomas. HTLV -1 was isolated 1981 from the cell of patient with cutaneous T-cell lymphoma. It was induced from tumor cell by exposure to iodo – deoxy uridin . Its RNA and proteins are different from those of all other retroviruses. IN addition to cancer, HTLV is the cause of tropical spastic Para paresis and autoimmune disease in which progressive weakness of the leg occurs. HTLV – 1 may cause cancer by a mechanism different from that of other retroviruses. It has no viral oncogen . Rather it has two special genes ( in addition to the standard retroviral genes gag , pol , and env ) called tax and rex they play a role in oncogenesis by regulating mRNA transcription and translation. The tax protein has two activities : 1- It acts on the viral long terminal repeat (LTR) sequences to stimulate viral mRNA synthesis. 2- It induces NF-KB which stimulate the production of interleukin – 2 (IL- 2)and the IL- 2 receptor. The increase in the levels of IL – 2 and its receptors stimulates the Tcells to continue growing , thus increasing the likelihood that the cells will become malignant. The Rex protein determines which viral mRNA s can exit the nucleus and inter the cytoplasm to be translated. Examples of other viruses causing human cancer : Human papilloma virus ( HPV )>>>>This virus definitely known to progress to form carcinomas , especially in an immunocompromised person . Papilloma virus are members of the family Papilloma viridae ( formerly Papovaviridae ). Carcinogenesis.by Human Papilloma Virus (HPV) involve two proteins encoded by this virus(HPV) gene E6 and E7 that interfere with the activity of proteins encoded by two tumor suppressor genes , P53 and Rb (retinoblastoma). In most papilloma tumor cell , the viral DNA is integrated into the cellular DNA and the E6 and E7 protein are produced. ******Epstein – Barr virus ( EBV) EbV is herpes virus that was isolated from the cells of an East African individual with burkitt's lymphoma. EBV , the cause of infectious mononucleosis , transform B lymphocytes in culture and causes lymphomas in marmoset monkeys . It also associated with nasopharyngeal carcinoma , a tumor that occure primarly in china and with thymic carcinoma and B – cell lymphoma in United state . **** only a small fraction of the many copies of EBV DNA is integrated , most viral DNA is in the form of closed circle in the cytoplasm . #@* Hepatitis B Virus cause hepatocellular carcinoma ( hepatoma) , a chronic hepatitis B infection commonly cause cirrhosis of liver. <<< … >>> Hepatitis - C virus (HCV ): chronic infection with HCV , like HBV , also predispose hepatocellular carcinoma. HCV is RNA VIRUS THAT HAVE NO ONCOGEN AND FORM NO DNA intermediate mediate during replication ,,,,,it cause chronic hepatitis which seem likely to be the main predisposing events. Human Herpes virus – 8 (HHV- 8) , also known as kaposi’s sarcoma – associated herpes virus, may cause kaposi’s sarcoma. The DNA of the virus has been detected in the sarcomas cell . but the role of the virus in oncogenesis remained to be determined. Transmission of Human Viruses 1- vertical transmission : a- by sperm or ova , example HIV …..high incidence of tumor b- through placenta, example Rubella and Measles c-Brest milk example , HIV and CMV …… high incidence of tumor 2- Horizontal transmission …..Probably does not occur in human.