This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity is a risk factor in many of the major chronic diseases that afflict our society, including coronary artery disease, diabetes mellitus, and cancer. Understanding the detailed molecular mechanisms involved in the control of cell cycle exit and initiation of terminal differentiation in adipogenic stem cells will open the door to rationally designed treatments that complement existing treatments to alleviate obesity and its side effects. 3T3L1 cells are a well-studied model system for the differentiation of adipocytes. Quiescent 3T3L1 cells express high levels of the Rb-related protein p130 but little if any p107. Over the first 24 hours after they are stimulated to differentiate, the expression of p107 increases to a high level while that of p130 drops. p107 and p130 return to their former levels as the cells complete differentiation. Data with protein kinase inhibitors suggest that the rapid induction of p107 is critical for differentiation but not necessary for proliferation. We hypothesize that the pocket proteins pRB, p107, and p130 carry out their critical roles in adipocyte cell cycle withdrawal and differentiation through their interactions with regulatory proteins, by which they stimulate or inhibit the activity of these regulatory proteins, setting in motion a chain of events that results in a permanent change in the ability of cells to proliferate. We plan to identify the protein-protein interaction of p107 during the early stages of terminal differentiation of 3T3L1 cells and determine which of the protein-protein interaction are critical for preadipocyte cell cycle withdrawal and terminal differentiation. The components of these complexes will be identified by mass spectrometry. These components will be targeted for disruption to determine their role in the differentiation of 3T3L1 cells.
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