The Pim protein kinases regulate energy metabolism and cell growth.

Zanna Beharry, Sandeep Mahajan, Marina Zemskova, Ying Wei Lin, Baby G. Tholanikunnel, Zuping Xia, Charles D. Smith, Andrew Kraft

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)528-533
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number2
DOIs
StatePublished - Jan 11 2011
Externally publishedYes

Fingerprint

Protein Kinases
Energy Metabolism
Fibroblasts
Knockout Mice
Adenosine Monophosphate
Growth
Sirolimus
Proteins
AMP-Activated Protein Kinases
proto-oncogene proteins pim
Protein-Serine-Threonine Kinases
Organelle Biogenesis
Glycolysis
Hematologic Neoplasms
Small Interfering RNA
Cell Survival
Adenosine Triphosphate
Phosphorylation
Enzymes
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

The Pim protein kinases regulate energy metabolism and cell growth. / Beharry, Zanna; Mahajan, Sandeep; Zemskova, Marina; Lin, Ying Wei; Tholanikunnel, Baby G.; Xia, Zuping; Smith, Charles D.; Kraft, Andrew.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 2, 11.01.2011, p. 528-533.

Research output: Contribution to journalArticle

Beharry, Zanna ; Mahajan, Sandeep ; Zemskova, Marina ; Lin, Ying Wei ; Tholanikunnel, Baby G. ; Xia, Zuping ; Smith, Charles D. ; Kraft, Andrew. / The Pim protein kinases regulate energy metabolism and cell growth. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 2. pp. 528-533.
@article{8cb51303b49a4b938b81eede2d2043ae,
title = "The Pim protein kinases regulate energy metabolism and cell growth.",
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 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.",
author = "Zanna Beharry and Sandeep Mahajan and Marina Zemskova and Lin, {Ying Wei} and Tholanikunnel, {Baby G.} and Zuping Xia and Smith, {Charles D.} and Andrew Kraft",
year = "2011",
month = "1",
day = "11",
doi = "10.1073/pnas.1013214108",
language = "English (US)",
volume = "108",
pages = "528--533",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "2",

}

TY - JOUR

T1 - The Pim protein kinases regulate energy metabolism and cell growth.

AU - Beharry, Zanna

AU - Mahajan, Sandeep

AU - Zemskova, Marina

AU - Lin, Ying Wei

AU - Tholanikunnel, Baby G.

AU - Xia, Zuping

AU - Smith, Charles D.

AU - Kraft, Andrew

PY - 2011/1/11

Y1 - 2011/1/11

N2 - 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 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.

AB - 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 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.

UR - http://www.scopus.com/inward/record.url?scp=79952271999&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952271999&partnerID=8YFLogxK

U2 - 10.1073/pnas.1013214108

DO - 10.1073/pnas.1013214108

M3 - Article

C2 - 21187426

AN - SCOPUS:79952271999

VL - 108

SP - 528

EP - 533

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 2

ER -