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Regulation of Peroxisome Proliferator Activated Receptor (PPAR)‐ α by Murine Double Minute 2 (MDM2)
Author(s) -
Gopinathan Lakshmi,
Han Daniel B,
Heuvel John P Vanden
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a254-d
Subject(s) - nuclear receptor , transactivation , peroxisome proliferator activated receptor , mdm2 , ubiquitin ligase , microbiology and biotechnology , ubiquitin , glucose homeostasis , biology , transcription factor , receptor , chemistry , cancer research , endocrinology , biochemistry , insulin resistance , insulin , gene
PPARs (PPARα, PPARβ, and PPARγ) are nuclear hormone receptors that regulate genes involved in lipid metabolism, glucose homeostasis, inflammation, and hepato‐carcinogenesis. Alterations in these pathways are key causes for some major modern day pathologies such as diabetes, obesity, cardiovascular diseases, and cancer. The ubiquitin‐proteasome system is fast emerging as a major regulator of nuclear receptor dynamics. However, studies of PPAR regulation by ubiquitination are few, representing a major gap in understanding their role in cellular metabolism. We have identified, for the first time, a ubiquitin ligase, MDM2 that interacts with PPARα. Overexpression of MDM2 enhanced PPARα agonist, Wy‐14,643‐induced PPARα transactivation, using a PPAR‐response element driven luciferase reporter construct. MDM2 siRNA attenuated Wy‐14,643‐induced increase in mRNA levels of PPARα target genes. This study links PPARα to an important cell fate pathway (MDM2‐p53). It also adds to the intriguing links observed between ubiquitination and transcription, wherein the ubiquitin‐proteasome pathway that classically targets proteins to degradation, also functions in transcriptional activation. Supported by NIH ES007799