The Pim protein kinases regulate energy metabolism and cell growth
| Autor: | Sandeep Mahajan, Andrew S. Kraft, Zuping Xia, Charles D. Smith, Ying Wei Lin, Marina Zemskova, Baby G. Tholanikunnel, Zanna Beharry |
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| Rok vydání: | 2010 |
| Předmět: |
Cell Survival
mTORC1 Mechanistic Target of Rapamycin Complex 1 Biology Gene Expression Regulation Enzymologic Proto-Oncogene Proteins c-myc Mice Proto-Oncogene Proteins c-pim-1 Cell Line Tumor hemic and lymphatic diseases Animals Humans Protein kinase A Heat-Shock Proteins Cell Proliferation Multidisciplinary Kinase Cell growth TOR Serine-Threonine Kinases Proteins AMPK Biological Sciences Fibroblasts Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Cell biology Gene Expression Regulation Neoplastic Mitochondrial biogenesis Multiprotein Complexes Trans-Activators Phosphorylation K562 Cells Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 108:528-533 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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 AMP∶ATP 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 1α (PGC-1α), enzymes capable of regulating glycolysis and mitochondrial biogenesis, which were diminished in TKO MEFs. Overexpression of PGC-1α 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-1α protein levels and cell growth. |
| Databáze: | OpenAIRE |
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