| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Lee, Yun Kyung Lee, Sean Bong Kim, Jihyun Chung, Jay H. Park, Jun Hong Kang, Hyeog Kang, Hong-jun Chang, Ji Suk Mcpherron, Alexandra C. |
| Description |
Author Affiliation: Park JH ( Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112); Kang HJ ( Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112); Lee YK ( Molecular Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892); Kang H ( Laboratory of Obesity and Aging Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.); Kim J ( Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA 70808); Chung JH ( Laboratory of Obesity and Aging Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.); Chang JS ( Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA 70808); McPherron AC ( Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.); Lee SB ( Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112); |
| 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-1 ), a central regulator of mitochondria biogenesis, function, and cellular energy metabolism. EWS inactivation leads to increased ubiquitination and proteolysis of PGC-1 via proteasome pathway. Complementation of EWS in Ews-deficient cells restores PGC-1 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-1 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 ß-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-1 protein stability, and further implicate altered mitochondrial and energy metabolism in cancers harboring the EWS translocation. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
19 |
| Volume Number |
112 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2015-05-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Mitochondria Metabolism RNA-Binding Protein EWS Antagonists & Inhibitors Transcription Factors Adipose Tissue, Brown Animals DNA, Mitochondrial Energy Metabolism F-Box Proteins Fatty Acids Chemistry Gene Expression Profiling HEK293 Cells Homeostasis Liver Mice Mice, Inbred C57BL Mice, Knockout Microscopy, Electron, Transmission Muscle, Skeletal Oxygen Protein Conformation Ubiquitin Ubiquitin-Protein Ligases Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
