This application is for competitive renewal of a project that, through its entire course, has had as its objective the identification of mechanisms that regulate cell growth and proliferation in normal hepatocytes, facultative liver stem cells and hepatic carcinogenesis. To accomplish this objective, we have focused our efforts on signal transduction mechanisms that control hepatocyte growth and proliferation during late gestation in the rat and mouse. Our previous work on this project has defined a fetal hepatocyte signaling phenotype that differs from that seen in adult rat hepatocytes that are stimulated to proliferate in response to reduced hepatic mass (partial hepatectomy). The components of this phenotype include characteristics typical of cancer cells: lack of dependence on growth factor signaling, resistance to apoptosis and upregulation of a spectrum of onco-fetal genes, including the proto-oncogene c-myc. During the last cycle of this project, we identified a new mechanism, nucleolar localization, by which the function of the c-Myc protein may be controlled. We also demonstrated that fetal hepatocytes proliferating in vivo are resistant to the growth inhibitory effects of rapamycin, an inhibitor of the nutrient-sensing kinase mTOR. These findings led us to focus this renewal application on key signaling events that converge on the control of ribosome biogenesis and global protein translation in late gestation rodent hepatocytes.
Specific Aim 1 will focus on c-Myc in the control of ribosome biogenesis and as an upstream regulator of the expression and function of the Ser/Thr phosphatase PP2A.
Specific Aim 2 will focus on signaling mechanisms involving PP2A that modulate c-Myc function and contribute to the resistance of fetal hepatocytes and transformed hepatic cell lines to the growth inhibitory effects of rapamycin.
In Specific Aim 3, we will use genomic and proteomic approaches to identify mechanisms that regulate c-Myc and PP2A via mTOR, taking advantage of a panel of hepatic cells that show varying degrees of rapamycin-sensitivity, from highly sensitive to highly resistant. The ultimate benefit of this work to public health relates to its potential for understanding mechanisms involved in normal and liver cell growth. More specifically, we hope to advance our understanding of mechanisms accounting for rapamycin-resistance, a subject with immediate relevance to cancer therapy, the physiological mechanisms involved in nutrient regulation of cell proliferation, and ways in which normal cellular growth control mechanisms can be perturbed, as is the case during the process of hepatic carcinogenesis.
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