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Akt requires glucose metabolism to suppress puma expression and prevent apoptosis of leukemic T cells.

Publication ,  Journal Article
Coloff, JL; Mason, EF; Altman, BJ; Gerriets, VA; Liu, T; Nichols, AN; Zhao, Y; Wofford, JA; Jacobs, SR; Ilkayeva, O; Garrison, SP ...
Published in: J Biol Chem
February 18, 2011

The PI3K/Akt pathway is activated in stimulated cells and in many cancers to promote glucose metabolism and prevent cell death. Although inhibition of Akt-mediated cell survival may provide a means to eliminate cancer cells, this survival pathway remains incompletely understood. In particular, unlike anti-apoptotic Bcl-2 family proteins that prevent apoptosis independent of glucose, Akt requires glucose metabolism to inhibit cell death. This glucose dependence may occur in part through metabolic regulation of pro-apoptotic Bcl-2 family proteins. Here, we show that activated Akt relies on glycolysis to inhibit induction of Puma, which was uniquely sensitive to metabolic status among pro-apoptotic Bcl-2 family members and was rapidly up-regulated in glucose-deficient conditions. Importantly, preventing Puma expression was critical for Akt-mediated cell survival, as Puma deficiency protected cells from glucose deprivation and Akt could not readily block Puma-mediated apoptosis. In contrast, the pro-apoptotic Bcl-2 family protein Bim was induced normally even when constitutively active Akt was expressed, yet Akt could provide protection from Bim cytotoxicity. Up-regulation of Puma appeared mediated by decreased availability of mitochondrial metabolites rather than glycolysis itself, as alternative mitochondrial fuels could suppress Puma induction and apoptosis upon glucose deprivation. Metabolic regulation of Puma was mediated through combined p53-dependent transcriptional induction and control of Puma protein stability, with Puma degraded in nutrient-replete conditions and long lived in nutrient deficiency. Together, these data identify a key role for Bcl-2 family proteins in Akt-mediated cell survival that may be critical in normal immunity and in cancer through Akt-dependent stimulation of glycolysis to suppress Puma expression.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

February 18, 2011

Volume

286

Issue

7

Start / End Page

5921 / 5933

Location

United States

Related Subject Headings

  • Up-Regulation
  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Mitochondria
  • Mice
  • Membrane Proteins
 

Citation

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Coloff, J. L., Mason, E. F., Altman, B. J., Gerriets, V. A., Liu, T., Nichols, A. N., … Rathmell, J. C. (2011). Akt requires glucose metabolism to suppress puma expression and prevent apoptosis of leukemic T cells. J Biol Chem, 286(7), 5921–5933. https://doi.org/10.1074/jbc.M110.179101
Coloff, Jonathan L., Emily F. Mason, Brian J. Altman, Valerie A. Gerriets, Tingyu Liu, Amanda N. Nichols, Yuxing Zhao, et al. “Akt requires glucose metabolism to suppress puma expression and prevent apoptosis of leukemic T cells.J Biol Chem 286, no. 7 (February 18, 2011): 5921–33. https://doi.org/10.1074/jbc.M110.179101.
Coloff JL, Mason EF, Altman BJ, Gerriets VA, Liu T, Nichols AN, et al. Akt requires glucose metabolism to suppress puma expression and prevent apoptosis of leukemic T cells. J Biol Chem. 2011 Feb 18;286(7):5921–33.
Coloff, Jonathan L., et al. “Akt requires glucose metabolism to suppress puma expression and prevent apoptosis of leukemic T cells.J Biol Chem, vol. 286, no. 7, Feb. 2011, pp. 5921–33. Pubmed, doi:10.1074/jbc.M110.179101.
Coloff JL, Mason EF, Altman BJ, Gerriets VA, Liu T, Nichols AN, Zhao Y, Wofford JA, Jacobs SR, Ilkayeva O, Garrison SP, Zambetti GP, Rathmell JC. Akt requires glucose metabolism to suppress puma expression and prevent apoptosis of leukemic T cells. J Biol Chem. 2011 Feb 18;286(7):5921–5933.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

February 18, 2011

Volume

286

Issue

7

Start / End Page

5921 / 5933

Location

United States

Related Subject Headings

  • Up-Regulation
  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Mitochondria
  • Mice
  • Membrane Proteins