Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-κB-dependent pathway

David Joyce, Boumediene Bouzahzah, Maofu Fu, Chris Albanese, Mark D'Amico, Jay Steer, Joshua U. Klein, Richard J. Lee, Jeffrey E. Segall, John K. Westwick, Channing J. Der, Richard G. Pestell

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251 Scopus citations

Abstract

The small GTP-binding protein Rac1, a member of the Ras superfamily, plays a fundamental role in cytoskeleton reorganization, cellular transformation, the induction of DNA synthesis, and superoxide production. Cyclin D1 abundance is rate-limiting in normal G1 phase progression, and the abundance of cyclin D1 is induced by activating mutations of both Ras and Rac1. Nuclear factor-κB (NF-κB) proteins consist of cytoplasmic hetero- or homodimeric Rel-related proteins complexed to a member of the IκB family of inhibitor proteins. In the current studies, activating mutants of Rac1 (Rac(Leu-61), Rac(Val-12)) induced cyclin D1 expression and the cyclin D1 promoter in NIH 3T3 cells. Induction of cyclin D1 by Rac1 required both an NF-κB and an ATF-2 binding site. Inhibiting NF-κB by overexpression of an NF-κB trans-dominant inhibitor (nonphosphorylatable IκBα) reduced cyclin D1 promoter activation by the Rac1 mutants, placing NF-κB in a pathway of Rac1 activation of cyclin D1. Specific amino acid mutations in the amino- terminal effector domain of Rac(Leu-61) had comparable effects on NF-κB transcriptional activity and activation of the cyclin D1 promoter. The NF-κB factors Rel A (p65) and NF-κB1 (p50) induced the cyclin D1 promoter, requiring both the NF-κB binding site and the ATF-2 site. Stable overexpression of Rac(Leu-61) increased binding of Rel A and NF-κB1 to the cyclin D1 promoter NF-κB site. Activation of Rac1 in NIH 3T3 cells induces both NF-κB binding and activity and enhances expression of cyclin D1 through an NF-κB and ATF-2 site in the proximal promoter, suggesting a critical role for NF-κB in cell cycle regulation through cyclin D1 and Rac1.

Original languageEnglish (US)
Pages (from-to)25245-25249
Number of pages5
JournalJournal of Biological Chemistry
Volume274
Issue number36
DOIs
StatePublished - Sep 3 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Joyce, D., Bouzahzah, B., Fu, M., Albanese, C., D'Amico, M., Steer, J., Klein, J. U., Lee, R. J., Segall, J. E., Westwick, J. K., Der, C. J., & Pestell, R. G. (1999). Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-κB-dependent pathway. Journal of Biological Chemistry, 274(36), 25245-25249. https://doi.org/10.1074/jbc.274.36.25245