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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Zemskova, Marina Beharry, Zanna Mahajan, Sandeep Kraft, Andrew S. Tholanikunnel, Baby G. Lin, Ying-wei Xia, Zuping Smith, Charles D. |
| Description | Author Affiliation: Beharry Z ( Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, USA.); |
| Abstract | The serine/threonine Pim kinases are overexpressed in solid cancers and hematologic malignancies and promote cell growth and survival. Here, we find that a novel Pim kinase inhibitor, SMI-4a, or Pim-1 siRNA blocked the rapamycin-sensitive mammalian target of rapamycin (mTORC1) activity by stimulating the phosphorylation and thus activating the mTORC1 negative regulator AMP-dependent protein kinase (AMPK). Mouse embryonic fibroblasts (MEFs) deficient for all three Pim kinases [triple knockout (TKO) MEFs] demonstrated activated AMPK driven by elevated ratios of AMPATP relative to wild-type MEFs. Consistent with these findings, TKO MEFs were found to grow slowly in culture and have decreased rates of protein synthesis secondary to a diminished amount of 5'-cap-dependent translation. Pim-3 expression alone in TKO MEFs was sufficient to reverse AMPK activation, increase protein synthesis, and drive MEF growth similar to wild type. Pim-3 expression was found to markedly increase the protein levels of both c-Myc and the peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1 ), enzymes capable of regulating glycolysis and mitochondrial biogenesis, which were diminished in TKO MEFs. Overexpression of PGC-1 in TKO MEFs elevated ATP levels and inhibited the activation of AMPK. These results demonstrate the Pim kinase-mediated control of energy metabolism and thus regulation of AMPK activity. We identify an important role for Pim-3 in modulating c-Myc and PGC-1 protein levels and cell growth. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 2 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Proteins Metabolism Proto-Oncogene Proteins C-pim-1 Trans-Activators Animals Cell Line, Tumor Cell Proliferation Cell Survival Fibroblasts Heat-Shock Proteins K562 Cells Mice Multiprotein Complexes Proto-Oncogene Proteins C-myc TOR Serine-Threonine Kinases Transcription Factors Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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