(from the applicant): Cyclin D1 is a tightly regulated cell cycle control molecule that functions as a critical sensor of extracellular growth stimulatory and inhibitory signals and a key determinant of progression through G1 phase. Aberrant expression of cyclin D1 is one of the most frequent abnormalities in human cancer, and is believed to play an important role in tumorigenesis. Understanding of the mechanisms underlying control of cyclin D1 accumulation under normal and pathological conditions is, therefore, of key importance. Our studies have identified protein kinase C a (PKCa) as a novel regulator of cyclin D1 expression in intestinal epithelial cells. PKCa exhibits growth inhibitory and tumor suppressor properties in the intestine, and its expression is lost early during intestinal tumor development. Based on extensive new data, strategies are proposed to address the hypothesis that PKCa signaling plays a critical role in regulating the expression of cyclin D1 in intestinal cells, and that disruption of PKCa-mediated cyclin D1 control contributes to intestinal neoplasia. The following key findings provide the foundation for this hypothesis: (a) PKCa activity represses cyclin D1 accumulation in non-transformed intestinal cells by two mechanisms: inhibition of cap-dependent translation initiation and blockade of cyclin D1 mRNA accumulation;(b) inhibitory effects of PKCa on cyclin D1 translation involve activation of the translational repressor 4E-BP1;(c) loss of PKCa signaling is associated with hyperinduction of cyclin D1 mRNA and protein and increased cell proliferation, and (c) restoration of PKCa in colon cancer cells represses cyclin D1 mRNA and protein and inhibits anchorage-independent growth. To explore further the link between PKCa signaling and control of cyclin D1 accumulation in intestinal cells, the following Specific Aims will be addressed: (1) To determine the mechanisms by which PKCa signaling modulates PP2A activity and 4E-BP1 hypophosphorylation/activation to effect cyclin D1 loss in intestinal cells, (2) To explore the role of Id1 suppression in PKCa-induced downregulation of cyclin D1 in normal and neoplastic intestinal cells, (3) To investigate the mechanisms involved in cyclin D1 mRNA hyperinduction associated with loss of PKCa signaling in intestinal epithelial cells, and (4) To explore the role of PKCa signaling in regulation of cyclin D1 levels and maintenance of intestinal homeostasis in vivo. The long-term goals of this project are to understand the mechanisms that orchestrate the process of intestinal epithelial renewal under normal conditions, to determine how intestinal cells overcome these controls to produce tumors, and to identify novel targets for prevention and therapy of intestinal cancer.
Cyclin D1 plays a critical role in regulation of cell growth and survival. Although increased expression of this molecule is one of the most common abnormalities in human cancer, the mechanisms underlying its aberrant accumulation are poorly understood. We have identified PKCa, which is lost early during intestinal tumorigenesis, as a novel repressor of cyclin D1 levels in intestinal cells. Understanding of the interplay between PKCa and cyclin D1 may identify new leads for prevention and/or therapy of intestinal tumors.
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