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Tumor suppressor MMAC/PTEN inhibits cytokine-induced NFkappaB activation without interfering with the IkappaB degradation pathway.

Publication ,  Journal Article
Koul, D; Yao, Y; Abbruzzese, JL; Yung, WK; Reddy, SA
Published in: J Biol Chem
April 6, 2001

The phosphoinositide 3-kinase (PI 3-kinase) pathway has been implicated in the activation of the proinflammatory transcription factor nuclear factor kappaB (NFkappaB). To investigate the role of this pathway in NFkappaB activation, we employed mutated in multiple advanced cancers/phosphatase and tensin homologue (MMAC/PTEN), a natural antagonist of PI 3-kinase activity. Our results show that cytokine-induced DNA binding and transcriptional activities of NFkappaB were both inhibited in a glioma cell line that was stably transfected with MMAC/PTEN. The ability of interleukin-1 (IL-1) to induce inhibitor (IkappaB) degradation or nuclear translocation of NFkappaB was, however, unaffected by MMAC/PTEN expression, suggesting that PI 3-kinase utilizes another equally important mechanism to control NFkappaB activation. It is conceivable that NFkappaB is directly phosphorylated through such a mechanism because treatment with protein phosphatase 2A significantly reduced its DNA binding activity. Moreover, IL-1-induced phosphorylation of p50 NFkappaB was potently inhibited in MMAC/PTEN-expressing cells. Whereas the mediators of NFkappaB phosphorylation remain to be identified, IL-1 was found to induce physical interactions between the PI 3-kinase target Akt kinase and the IkappaB.IkappaB kinase complex. Physical interactions between these proteins were antagonized by MMAC/PTEN consistent with their potential involvement in NFkappaB activation. Taken together, our observations suggest that PI 3-kinase regulates NFkappaB activation through a novel phosphorylation-dependent mechanism.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

April 6, 2001

Volume

276

Issue

14

Start / End Page

11402 / 11408

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Transfection
  • Transcription, Genetic
  • Signal Transduction
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • NF-kappa B
  • Humans
  • Gene Expression Regulation, Neoplastic
 

Citation

APA
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ICMJE
MLA
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Koul, D., Yao, Y., Abbruzzese, J. L., Yung, W. K., & Reddy, S. A. (2001). Tumor suppressor MMAC/PTEN inhibits cytokine-induced NFkappaB activation without interfering with the IkappaB degradation pathway. J Biol Chem, 276(14), 11402–11408. https://doi.org/10.1074/jbc.M007806200
Koul, D., Y. Yao, J. L. Abbruzzese, W. K. Yung, and S. A. Reddy. “Tumor suppressor MMAC/PTEN inhibits cytokine-induced NFkappaB activation without interfering with the IkappaB degradation pathway.J Biol Chem 276, no. 14 (April 6, 2001): 11402–8. https://doi.org/10.1074/jbc.M007806200.
Koul D, Yao Y, Abbruzzese JL, Yung WK, Reddy SA. Tumor suppressor MMAC/PTEN inhibits cytokine-induced NFkappaB activation without interfering with the IkappaB degradation pathway. J Biol Chem. 2001 Apr 6;276(14):11402–8.
Koul, D., et al. “Tumor suppressor MMAC/PTEN inhibits cytokine-induced NFkappaB activation without interfering with the IkappaB degradation pathway.J Biol Chem, vol. 276, no. 14, Apr. 2001, pp. 11402–08. Pubmed, doi:10.1074/jbc.M007806200.
Koul D, Yao Y, Abbruzzese JL, Yung WK, Reddy SA. Tumor suppressor MMAC/PTEN inhibits cytokine-induced NFkappaB activation without interfering with the IkappaB degradation pathway. J Biol Chem. 2001 Apr 6;276(14):11402–11408.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

April 6, 2001

Volume

276

Issue

14

Start / End Page

11402 / 11408

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Transfection
  • Transcription, Genetic
  • Signal Transduction
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • NF-kappa B
  • Humans
  • Gene Expression Regulation, Neoplastic