Development of liver tumors involves alterations in expression of many genes. The elucidation of molecular mechanisms that regulate gene expression in normal cells and in cancer cells is an important step for the development of therapeutic treatments of the tumor. Translation of proteins from mRNAs is one of the critical events in the expression of the genes. My laboratory investigates biological activities of RNA CUG triplet repeat binding protein, CUGBP1, and the role of this protein in liver proliferation and in liver tumors. In the liver, CUGBP1 regulates translation of several proteins including a member of C/EBP family, C/EBP?, which is a key regulator of liver proliferation. CUGBP1 binds to the 5' region of C/EBP? mRNA and increases translation of a dominant negative molecule C/EBP?-LIP, which inhibits biological activities of full-length C/EBP proteins and promotes liver proliferation. We have recently identified a new target of CUGBP1 in the liver. We obtain evidence that CUGBP1 binds to the 5' region of mRNA coding for a histone deacetylase 1, HDAC1, and increases translation of HDAC1 protein in tumor liver. We found that the translational activity of CUGBP1 is controlled mainly on the level of phosphorylation of CUGBP1. In tumor livers and in livers proliferating after partial hepatectomy (PH), CUGBP1 is hyper-phosphorylated and this phosphorylation increases translational activities of CUGBP1. We have found that cdk4 is a kinase which phosphorylates CUGBP1 and increases its translational activity. Therefore, the major hypothesis of this application is that the cdk4-mediated activation of CUGBP1 in the liver leads to the increased translation of C/EBP?-LIP and HDAC1 and to development of tumor (see diagram on the left). Consistent with this hypothesis, levels of cyclin D1 and cyclin D3, which are activators of cdk4, are increased in cytoplasmic extracts of human liver tumors and in cytoplasm of mouse liver proliferating after partial hepatectomy.
Specific Aim 1 examines mechanisms by which proliferating livers increase amounts of cdk4-D-type cyclins complexes in cytoplasm.
Specific Aims 2 and 3 determine the role CUGBP1-C/EBP?-LIP and CUGBP1-HDAC1 pathways in liver proliferation. We will test the hypothesis that CUGBP1-mediated elevation of HDAC1 inhibits promoters of liver specific tumor suppressor genes such as C/EBPa. In this application, we will also determine mechanisms by which liver blocks growth promotion activities of C/EBP?-LIP under certain conditions such as Acute Phase Response. The understanding of the mechanisms of the elevation of C/EBP?-LIP and HDAC1 in tumor will help to develop approaches to prevent malignant transformations in the liver. Public Health Relevance: This project investigates the role of RNA binding protein CUGBP1 in development of liver tumors and in the liver proliferation after partial hepatectomy (PH). The goals of this application are 1) to examine the role of RNA binding proteins in the development of liver tumors; 2) elucidate mechanisms by which proliferating livers activate RNA binding proteins; and 3) determine down-stream targets of RNA binding protein CUGBP1 in proliferating livers. The elucidation of molecular mechanisms of malignant transformations in liver will provide basement for the development of therapeutic approaches to prevent tumors. ? ? ?
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