The focus of this application is on adipocyte differentiation. Adipocyte differentiation requires the coordinated expression of numerous gene involved in growth. Early during the differentiation process, adipocyte precursors along with many other cell types, are required to re-enter the cell cycle and undergo a clonal expansion phase prior to growth arrest and terminal differentiation. The pathways involved in regulation of these early cell cycle events are largely unknown. Studies in tumor cells as well as non-malignant cells suggest that members of the retinoblastoma family of proteins play important roles in regulating cell cycle progression, particularly through their interaction with the E2F family of transcription factors. The PI has identified a regulation in p130 and p107 expression in differentiating 3T3-L1 cells (a model of adipocyte differentiation). This """"""""p130:p107 switch"""""""" correlates with early mitotic clonal expansion. They also present data suggesting that disruption of the p130:p107 switch by TNF alpha may explain the well described TNF alpha-induced inhibition of adipogenesis. They also present data that pRb is involved in transcriptional control of adipocyte genes. Based on these findings, they hypothesize that the retinoblastoma family of proteins is involved in adipocyte differentiation. The application proposes experiments designed to examine mechanisms through which these interactions occur.
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