Ubiquitin-dependent regulation of PPARgamma

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DESCRIPTION (provided by applicant): Obesity is a primary risk factor for type 2 diabetes, metabolic syndrome and cardiovascular diseases such as hypertension. These chronic disorders are predicted to increase with the aging population. Adipose tissue expresses high levels of the peroxisome proliferator-activated receptor, PPARgamma, the master switch in adipose cell formation. Recent studies show that modulation of PPARgamma levels improves insulin sensitivity and protects against insulin resistance associated with aging. Our recent studies indicate that regulation of PPARgamma levels by the ubiquitin-proteasome system is linked to the control of PPARgamma activity. In addition, we have learned that SUMO-1 modification of PPARgamma in the N-terminal ligand-independent activation (AF-1) domain affects PPARgamma stability and activity. We hypothesize that ubiquitin-dependent degradation is an important regulator of PPARgamma activity in adipocytes and that the N-terminal AF-1 domain of PPARgamma is a determinant of PPARgamma ubiquitin-proteasome mediated degradation. Our goals in this proposal are to define the region of PPARgamma that is required for the regulated degradation of PPARgamma and to examine the relationship between SUMOylation of PPARgamma at lysine 107 and modification of PPARgamma by ubiquitin. Our long-term goal is to further the development of PPARgamma-directed therapeutics in the treatment of obesity-related disorders by understanding how PPARgamma protein levels are regulated. In Specific Aim 1, we will define the region of PPARgamma that is recognized by the ubiquitin-proteasome system. These studies will focus on the AF-1 or AF-2 activation domains of PPARgamma2. In specific aim 2, we will examine the relationship between SUMOylation of lysine 107 and ubiquitylation of PPARgamma2 and how this relates to PPARgamma activity. Information obtained from examining the molecular mechanisms regulating PPARgamma protein levels may provide new therapeutic targets in treating obesity, type 2 diabetes, and related cardiovascular diseases.