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Reciprocal control of Forkhead box O 3a and c-Myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels.

Publication ,  Journal Article
Chandramohan, V; Jeay, S; Pianetti, S; Sonenshein, GE
Published in: J Immunol
May 1, 2004

B cell receptor (BCR) engagement of murine WEHI 231 immature B lymphoma cells leads sequentially to a drop in NF-kappa B and c-Myc, and induction of the p27(Kip1) cyclin-dependent kinase inhibitor, which promotes growth arrest and apoptosis. BCR engagement was recently shown to induce a drop in phosphatidylinositol 3-kinase (PI3K)/Akt signaling, preceding the increase in p27. As induction of p27 is due to an increase in gene transcription, we investigated the role of the Forkhead box O (FOXO) transcription factor family, which has been shown to potently induce p27 promoter activity. We demonstrate that pharmacologic inhibitors of PI3K or BCR engagement lead to decreased inactive cytoplasmic levels and increased active functional nuclear FOXO3a. In contrast, inhibition of PI3K/Akt signaling decreased the levels of NF-kappa B and c-Myc, which has been shown to repress p27 promoter activity. To test the effects of ectopic c-Myc on endogenous p27 levels, WEHI 231 cells stably expressing c-Myc or empty vector DNA were prepared. Ectopic c-Myc blocked the induction of p27 expression upon either inhibition of PI3K or BCR engagement. Thus, p27(Kip1) is coordinately regulated via two arms of a signaling pathway that are inversely controlled upon inhibition of PI3K: induction of the activator FOXO3a and down-regulation of the repressor c-Myc.

Duke Scholars

Published In

J Immunol

DOI

ISSN

0022-1767

Publication Date

May 1, 2004

Volume

172

Issue

9

Start / End Page

5522 / 5527

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Transcription Factors
  • Signal Transduction
  • Proto-Oncogene Proteins c-myc
  • Proliferating Cell Nuclear Antigen
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphatidylinositol 3-Kinases
  • NF-kappa B
  • Morpholines
  • Mice
 

Citation

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Chandramohan, V., Jeay, S., Pianetti, S., & Sonenshein, G. E. (2004). Reciprocal control of Forkhead box O 3a and c-Myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels. J Immunol, 172(9), 5522–5527. https://doi.org/10.4049/jimmunol.172.9.5522
Chandramohan, Vidyalakshmi, Sébastien Jeay, Stefania Pianetti, and Gail E. Sonenshein. “Reciprocal control of Forkhead box O 3a and c-Myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels.J Immunol 172, no. 9 (May 1, 2004): 5522–27. https://doi.org/10.4049/jimmunol.172.9.5522.
Chandramohan V, Jeay S, Pianetti S, Sonenshein GE. Reciprocal control of Forkhead box O 3a and c-Myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels. J Immunol. 2004 May 1;172(9):5522–7.
Chandramohan, Vidyalakshmi, et al. “Reciprocal control of Forkhead box O 3a and c-Myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels.J Immunol, vol. 172, no. 9, May 2004, pp. 5522–27. Pubmed, doi:10.4049/jimmunol.172.9.5522.
Chandramohan V, Jeay S, Pianetti S, Sonenshein GE. Reciprocal control of Forkhead box O 3a and c-Myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels. J Immunol. 2004 May 1;172(9):5522–5527.

Published In

J Immunol

DOI

ISSN

0022-1767

Publication Date

May 1, 2004

Volume

172

Issue

9

Start / End Page

5522 / 5527

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Transcription Factors
  • Signal Transduction
  • Proto-Oncogene Proteins c-myc
  • Proliferating Cell Nuclear Antigen
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphatidylinositol 3-Kinases
  • NF-kappa B
  • Morpholines
  • Mice