Analyse der Effekte des hepatotropen Cyanobakterientoxins Microcystin und des Hepatitis B- Virus- x Proteins auf die Zellzyklus- Regulation
|Other Titles:||Involvement of Hepatitis B virus X protein and cyanobacteria hepatotoxin microcystin in the etiology of HBV- associated HCC||Authors:||Nickeleit, Irina||Supervisor:||Vallbracht, Angelika||1. Expert:||Vallbracht, Angelika und Will, Hans||Abstract:||
Epidemiological studies have suggested synergistic interactions between chronic hepatitis B virus (HBV) infection and microcystin (MCYST) exposure in the etiology of hepatocellular carcinoma (HCC). As a potent inhibitor of protein phosphatase 1 and 2A could probably induce the hyperphosphorylation of tumorsuppressor proteins, retinoblastoma protein and p53, including their associated cell cycle proteins. The MCYST- mediated hyper-phosphorylation of pRb and p53 in HepG2 cells was confirmed by protein analytical methods and functinal transfection analysis with a luciferase reportergen system. Hyperphosphorylation of tumor suppressor proteins, mediated through inhibition of protein phosphatase 1 and 2A are involved in the deregulation of the cell cycle and a biochemical alternativly pathway of tumor promotion. In addition to prove the possibility of MCYST- associated functional inactivation of p53 we performed apoptosis assays and to consider the influence of MCYST of the subcellular localization of p53 using a p53-GFP- transfection system. The human hepatitis B virus x-protein (HBx) is suspected to play a role in the hepatocarcinogenic process by virtue of its capacity to transactivate oncogenes and serveral other cellular genes. We demonstrated confirmed by transient transfection assays with diverse specific luciferase reportergen systems that HBx is able to stimulate the cell cycle progression and influence the checkpionts controll. Finally, with cotransfection analyses in HepG2 we showed that that MCYST and HBx in combination deregulate the activity of cell cycle proteins such as p53,pRb, E2F and c-myc. Taken together, our results indicate that MCYST and HBx in an initiated human hepatoma cell culture system (HepG2) alone and in combination affected the activity of essential regulators of the G1 phase of the cell cycle.These datas suggest a molecular mechanism by which MCYST and HBx are likely to contribute to viral carcinogenesis.
|Issue Date:||11-Dec-2003||URN:||urn:nbn:de:gbv:46-diss000007647||Institution:||Universität Bremen||Faculty:||FB2 Biologie/Chemie|
|Appears in Collections:||Dissertationen|
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