Priority Research Papers:
Acetylation-defective mutants of Pparγ are associated with decreased lipid synthesis in breast cancer cells
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Lifeng Tian1, Chenguang Wang1, Fred K. Hagen2, Michael Gormley1, Sankar Addya1, Raymond Soccio3, Mathew C. Casimiro1, Jie Zhou1, Michael J. Powell1, Ping Xu4, Haiteng Deng5, Anthony A. Sauve4 and Richard G. Pestell1
1 Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
2 Department of Biochemistry and Biophysics, University of Rochester, Rochester, NY, USA
3 Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
4 Department of Pharmacology, Weill Medical College of Cornell University, York Avenue LC216, New York, NY, USA
5 Proteomics Resource Center, Rockefeller University, New York, NY, USA
Richard G. Pestell, email:
Chenguang Wang, email:
Keywords: acetylation; peroxisome proliferator-activated receptor gamma (Pparγ); nuclear receptors; silent mating type information regulation 2 homolog 1 (SIRT1); lipogenesis.
Received: JULY 18, 2014 Accepted: August 18, 2014 Published: August 19, 2014
In our prior publications we characterized a conserved acetylation motif (K(R)xxKK) of evolutionarily related nuclear receptors. Recent reports showed that peroxisome proliferator activated receptor gamma (PPARγ) deacetylation by SIRT1 is involved in delaying cellular senescence and maintaining the brown remodeling of white adipose tissue. However, it still remains unknown whether lysyl residues 154 and 155 (K154/155) of the conserved acetylation motif (RIHKK) in Pparγ1 are acetylated. Herein, we demonstrate that Pparγ1 is acetylated and regulated by both endogenous TSA-sensitive and NAD-dependent deacetylases. Acetylation of lysine 154 was identified by mass spectrometry (MS) while deacetylation of lysine 155 by SIRT1 was confirmed by in vitro deacetylation assay. An in vivo labeling assay revealed K154/K155 as bona fide acetylation sites. The conserved acetylation sites of Pparγ1 and the catalytic domain of SIRT1 are both required for the interaction between Pparγ1 and SIRT1. Sirt1 and Pparγ1 converge to govern lipid metabolism in vivo. Acetylation-defective mutants of Pparγ1 were associated with reduced lipid synthesis in ErbB2 overexpressing breast cancer cells. Together, these results suggest that the conserved lysyl residues K154/K155 of Pparγ1 are acetylated and play an important role in lipid synthesis in ErbB2-positive breast cancer cells.
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