The long-term goals of this proposal are directed towards understanding mechanisms of liver regeneration and hepatocarcinogenesis. Proto-oncogene cyclin D1 is a major cell-cycle protein that is necessary for normal adult hepatocyte proliferation. Many convergent intracellular pathways have been identified that regulate cyclin D1 expression in hepatocytes, but there are no reports that IKK? is among them. IKK? kinase is required for activation of transcription factor NF-KB and for the prevention of hepatocyte apoptosis mediated by cell-bound but not by circulating TNFa. New investigations have revealed that following 70% partial hepatectomy, mouse liver regeneration starts faster and the diethylnitrosamine- induced incidence of hepatocellular carcinoma (HCC) is higher in mice carrying targeted hepatocyte-specific IKK? deletions. In contrast, adult mouse liver regeneration is blunted and the incidence of HCC is attenuated in mice carrying cellular IKKB deletions throughout the liver including its hematopoietic cellular components. Available evidence further suggests that, in this mouse model of normal liver regeneration (in response to 70% partial hepatectomy) and chemical hepatocarcinogenesis, normal hepatocytes - not liver stem cells -- are precursors of compensatory proliferation and HCC. Thus, changes in growth regulatory systems that increase the probabilities of hepatocyte proliferation may well make such hepatocytes more sensitive to growth factors and to carcinogenic transformation. Therefore, owing to their relationship to chemical hepatocarcinogenesis, this proposal will focus on hepatocyte growth alterations related to IKK? in normal hepatocytes. Specifically, the observations suggest that IKK? is a bi-functional regulator of adult hepatocyte proliferation: directly inside hepatocytes;and, indirectly inside non-parenchymal liver cells. Such observations implicate tumor suppressor and tumor promoter roles for hepatocyte and non-parenchymal liver cell IKK?. Standard procedures of cellular and molecular biology, mouse genetics, and analyses of tissues and cells derived from specific strains of normal and knockout mice, will be used to investigate these predictions in adult liver cells. Accordingly, three specific aims will test the following hypotheses: 1] IKK? is a 'passive'negative regulator of adult hepatocyte proliferation;2] IKK? is required in nonparenchymal liver cells for provision of growth factors that stimulate adult hepatocyte proliferation;and, 3] Hepatocyte IKKI2, deletion facilitates precocious S-phase entry in growth-stimulated hepatocytes by increasing JNK1 and/or reducing JNK2 expression which prolong c-JUN expression, enhance AP-1 activation and stimulate early onset expression of cyclin D1. Attenuated co-regulated expression of hepatocyte IKK? and JNK2 may both facilitate hepatocyte proliferation and increase the susceptibility of hepatocytes to carcinogenesis.
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