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Molecular and Cellular Biology, March 2004, p. 2181-2189, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.2181-2189.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Control of Cyclin G2 mRNA Expression by Forkhead Transcription Factors: Novel Mechanism for Cell Cycle Control by Phosphoinositide 3-Kinase and Forkhead

Lorena Martínez-Gac,1 Miriam Marqués,1 Zaira García,1 Miguel R. Campanero,2 and Ana C. Carrera1*

Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Universidad Autónoma de Madrid, Cantoblanco, Madrid E-28049,1 Instituto de Investigaciones Biomédicas Alberto Sols, Madrid E-28029, Spain2

Received 21 July 2003/ Returned for modification 29 August 2003/ Accepted 4 December 2003

Cyclin G2 is an unconventional cyclin highly expressed in postmitotic cells. Unlike classical cyclins that promote cell cycle progression, cyclin G2 blocks cell cycle entry. Here we studied the mechanisms that regulate cyclin G2 mRNA expression during the cell cycle. Analysis of synchronized NIH 3T3 cell cultures showed elevated cyclin G2 mRNA expression levels at G0, with a considerable reduction as cells enter cell cycle. Downregulation of cyclin G2 mRNA levels requires activation of phosphoinositide 3-kinase, suggesting that this enzyme controls cyclin G2 mRNA expression. Because the phosphoinositide 3-kinase pathway inhibits the FoxO family of forkhead transcription factors, we examined the involvement of these factors in the regulation of cyclin G2 expression. We show that active forms of the forkhead transcription factor FoxO3a (FKHRL1) increase cyclin G2 mRNA levels. Cyclin G2 has forkhead consensus motifs in its promoter, which are transactivated by constitutive active FoxO3a forms. Finally, interference with forkhead-mediated transcription by overexpression of an inactive form decreases cyclin G2 mRNA expression levels. These results show that FoxO genes regulate cyclin G2 expression, illustrating a new role for phosphoinositide 3-kinase and FoxO transcription factors in the control of cell cycle entry.

* Corresponding author. Mailing address: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Carretera de Colmenar Km 15, Cantoblanco, Madrid E-28049, Spain. Phone: (34) 91/585-4846. Fax: (34) 91/372-0493. E-mail: acarrera{at}cnb.uam.es.

Molecular and Cellular Biology, March 2004, p. 2181-2189, Vol. 24, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.5.2181-2189.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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