Journal article
The Pim protein kinases regulate energy metabolism and cell growth
Proceedings of the National Academy of Sciences - PNAS, Vol.108(2), pp.528-533
01/11/2011
Handle:
https://hdl.handle.net/2376/113563
PMCID: PMC3021022
PMID: 21187426
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 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.
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Details
- Title
- The Pim protein kinases regulate energy metabolism and cell growth
- Creators
- Zanna Beharry - Department of Pharmaceutical and Biomedical Sciences, South Carolina College of PharmacySandeep Mahajan - Hollings Cancer CenterMarina Zemskova - Department of Cell and Molecular Pharmacology, andYing-Wei Lin - Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425Baby G Tholanikunnel - Hollings Cancer CenterZuping Xia - Department of Pharmaceutical and Biomedical Sciences, South Carolina College of PharmacyCharles D Smith - Department of Pharmaceutical and Biomedical Sciences, South Carolina College of PharmacyAndrew S Kraft - Hollings Cancer Center
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.108(2), pp.528-533
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Publisher
- National Academy of Sciences
- Identifiers
- 99900547322301842
- Language
- English
- Resource Type
- Journal article