Regulation of Cell Cycle Progression and Cellular Survival in Primary Rat Hepatocytes
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AbstractIn liver disease, irregular proliferation of hepatocytes is an important factor favoring hepatocarcinogenesis. The aim of this cell biological thesis has been to study the impact of epidermal growth factor (EGF) and cellular stress on the cell cycle- and cell survival machinery, mainly focusing on the MAP kinase pathway and PI3 kinase-Akt signalling.
EGF-induced proliferation is partly driven by the cyclic formation of cyclin-CDK complexes. By using a combination of immunological methods, it was demonstrated that PI3 kinase activity was essential for activation of CDK4. CDK4 in turn was crucial for CDK2 activity, which is an important event in the G1 phase of hepatocyte cell cycle progression. Growth factor-induced PI3 kinase activity also mediated p53 induction, and the induction of this tumor suppressor protein played a key role in cell cycle progression by regulating CDK4 and CDK2 activity, via p21Cip1.
EGF stimulation of hepatocytes activates the small GTP-protein Ras that signals through both ERK- and PI3 kinase pathways. Transient transfection of active- and inactive mutants of the Ras isoforms H-Ras and K-Ras, revealed different selectivity for the downstream mediators ERK and PI3 kinase. This distinction had impact on the iso-specific roles of H-Ras and K-Ras in survival and proliferation. It was further demonstrated that redox-activated ERK mediated survival from the cytoplasm and played an important role in adapting hepatocytes to a stressful environment.
LIST OF PAPERS
I Wierød L, Rosseland CM, Lindeman B, Oksvold MP, Grøsvik H, Skarpen E, and Huitfeldt HS. Activation of the p53-p21Cip1Pathway is Required for CDK2 Activation and Proliferation in Primary Rat Hepatocytes. Submitted November 2006.
II Wierød L, Rosseland CM, Lindeman B, Oksvold MP, Grøsvik H, Skarpen E, and Huitfeldt HS. CDK2 Regulation through PI3K and CDK4 is Necessary for Cell Cycle Progression of Primary Rat Hepatocytes. Cell Prolif. 2007 Aug;40(4):475-87. Abstract.
III Rosseland CM, Wierød L, Oksvold MP, Werner H, Østvold AC, Thoresen GH, Paulsen RE, Huitfeldt HS, and Skarpen E (2005). Cytoplasmic Retention of Peroxide-Activated ERK Provides Survival in Primary Cultures of Rat Hepatocytes. Hepatology, Vol. 42, No 1, 200-207. Abstract.
IV Rosseland CM, Wierød L, Flinder LI, Oksvold MP, Skarpen E, Huitfeldt HS. Distinct Functions of H-Ras and K-Ras in Proliferation and Survival of Primary Hepatocytes Due to Selective Avtivation of ERK and PI3K. Submitted December 2006.