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Map4k4 Negatively Regulates Peroxisome Proliferator-activated Receptor (PPAR) γ Protein Translation by Suppressing the Mammalian Target of Rapamycin (mTOR) Signaling Pathway in Cultured Adipocytes.
- Source :
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Journal of Biological Chemistry . 2/26/2010, Vol. 285 Issue 9, p6595-6603. 9p. - Publication Year :
- 2010
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Abstract
- The receptor peroxisome proliferator-activated receptor γ (PPARγ) is considered a master regulator of adipocyte differentiation and promotes glucose and lipid metabolism in mature adipocytes. We recently identified the yeast Sterile 20 (Ste20) protein kinase ortholog, Map4k4, in an RNA interference-based screen as an inhibitor of PPARγ expression in cultured adipocytes. Here, we show that RNA interference-mediated silencing of Map4k4 elevates the levels of both PPAR'γ1 and PPARγ2 proteins in 3T3-L1 adipocytes without affecting PPARγ mRNA levels, suggesting that Map4k4 regulates PPARγ at a post-transcriptional step. PPARγ degradation rates are remarkably rapid as measured in the presence of cycloheximide (t½ = 2 h), but silencing Map4k4 had no effect on PPARγ degradation. However, depletion of Map4k4 significantly enhances [35S]methionine/cysteine incorporation into proteins, suggesting that Map4k4 signaling decreases protein translation. We show a function of Map4k4 is to inhibit rapamycin-sensitive mamma- Jian target of rapamycin (mTOR) activity, decreasing AE-BP1 phosphorylation. In addition, our results show mTOR and 4E-BP1 are required for the increased PPARγ protein expression upon Map4k4 knockdown. Consistent with this concept, adenovirus-mediated expression of Map4k4 decreased PPARγ protein levels and mTOR phosphorylation. These data show that Map4k4 negatively regulates PPARγ post-transcriptionally, by attenuating mTOR signaling and a 4E-BP 1-dependent mechanism. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00219258
- Volume :
- 285
- Issue :
- 9
- Database :
- Academic Search Index
- Journal :
- Journal of Biological Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 48748836
- Full Text :
- https://doi.org/10.1074/jbc.M109.068502