GENES: STRUCTURE AND REGULATION
Degradation of the Peroxisome Proliferator-activated Receptor γ Is Linked to Ligand-dependent Activation*

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The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) γ is a ligand-activated transcription factor that regulates several crucial biological processes such as adipogenesis, glucose homeostasis, and cell growth. It is also the functional receptor for a new class of insulin-sensitizing drugs, the thiazolidinediones, now widely used in the treatment of type 2 diabetes mellitus. Here we report that PPARγ protein levels are significantly reduced in adipose cells and fibroblasts in response to specific ligands such as thiazolidinediones. Studies with several doses of different ligands illustrate that degradation of PPARγ correlates well with the ability of ligands to activate this receptor. However, analyses of PPARγ mutants show that, although degradation does not strictly depend on the transcriptional activity of the receptor, it is dependent upon the ligand-gated activation function 2 (AF2) domain. Proteasome inhibitors inhibited the down-regulation of PPARγ and ligand activation enhanced the ubiquitination of this receptor. These data indicate that, although ligand binding and activation of the AF2 domain increase the transcriptional function of PPARγ, these same processes also induce ubiquitination and subsequent degradation of this receptor by the proteasome.

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Published, JBC Papers in Press, March 16, 2000, DOI 10.1074/jbc.M001297200

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This work was supported by NIH Grant DKY1305 (to B. M. S); by fellowships from the Deutsche Forschungsgemeinschaft (to S. H.), the Medical Foundation (to S. H.), and European Molecular Biology (to G. A.); and by a postdoctoral National Research Service Award from the NIH (to H. M. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.