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Park 2015 Proc Natl Acad Sci USA

From Bioblast
Publications in the MiPMap
Park JH, Kang HJ, Lee YK, Kang H, Kim J, Chung JH, Chang JS, McPherron AC, Lee SB (2015) Inactivation of EWS reduces PGC-1α protein stability and mitochondrial homeostasis. Proc Natl Acad Sci USA 112:6074-9.

» PMID: 25918410

Park JH, Kang HJ, Lee YK, Kang H, Kim J, Chung JH, Chang JS, McPherron AC, Lee SB (2015) Proc Natl Acad Sci USA

Abstract: EWS (Ewing sarcoma) encodes an RNA/ssDNA binding protein that is frequently rearranged in a number of different cancers by chromosomal translocations. Physiologically, EWS has diverse and essential roles in various organ development and cellular processes. In this study, we uncovered a new role of EWS in mitochondrial homeostasis and energy metabolism. Loss of EWS leads to a significant decrease in mitochondria abundance and activity, which is caused by a rapid degradation of Peroxisome proliferator-activated receptor γ Coactivator (PGC-1α), a central regulator of mitochondria biogenesis, function, and cellular energy metabolism. EWS inactivation leads to increased ubiquitination and proteolysis of PGC-1α via proteasome pathway. Complementation of EWS in Ews-deficient cells restores PGC-1α and mitochondrial abundance. We found that expression of E3 ubiquitin ligase, FBXW7 (F-box/WD40 domain protein 7), is increased in the absence of Ews and depletion of Fbxw7 in Ews-null cells restores PGC-1α expression and mitochondrial density. Consistent with these findings, mitochondrial abundance and activity are significantly reduced in brown fat and skeletal muscles of Ews-deficient mice. Furthermore, expression of mitochondrial biogenesis, respiration and fatty acid β-oxidation genes is significantly reduced in the liver of Ews-null mice. These results demonstrate a novel role of EWS in mitochondrial and cellular energy homeostasis by controlling PGC-1α protein stability, and further implicate altered mitochondrial and energy metabolism in cancers harboring the EWS translocation. Keywords: EWS, PGC-1alpha, Energy metabolism, Mitochondria homeostasis, Protein stability, Adipocyte

O2k-Network Lab: US LA Baton Rouge Noland RC

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Cancer 

Organism: Mouse  Tissue;cell: Fat  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k