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Molecular and Cellular Biology, December 2005, p. 10940-10952, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.10940-10952.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inhibition of TFII-I-Dependent Cell Cycle Regulation by p53

Zana P. Desgranges,1 Jinwoo Ahn,2 Maria B. Lazebnik,3 Todd Ashworth,1 Caleb Lee,1 Richard C. Pestell,4 Naomi Rosenberg,1,3 Carol Prives,2 and Ananda L. Roy1,3*

Programs in Immunology,1 Genetics, Sackler School of Graduate Biomedical Sciences, Department of Pathology, Tufts University School of Medicine, 150 Harrison Avenue, Boston, Massachusetts 02111,3 Department of Biological Sciences, Columbia University, New York, New York 10027,2 Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, 3970 Reservoir Rd. NW, Washington, D.C. 20057-14684

Received 21 April 2005/ Returned for modification 13 July 2005/ Accepted 21 September 2005

The multifunctional transcription factor TFII-I is tyrosine phosphorylated in response to extracellular growth signals and transcriptionally activates growth-promoting genes. However, whether activation of TFII-I also directly affects the cell cycle profile is unknown. Here we show that under normal growth conditions, TFII-I is recruited to the cyclin D1 promoter and transcriptionally activates this gene. Most strikingly, upon cell cycle arrest resulting from genotoxic stress and p53 activation, TFII-I is ubiquitinated and targeted for proteasomal degradation in a p53- and ATM (ataxia telangiectasia mutated)-dependent manner. Consistent with a direct role of TFII-I in cell cycle regulation and cellular proliferation, stable and ectopic expression of wild-type TFII-I increases cyclin D1 levels, resulting in accelerated entry to and exit from S phase, and overcomes p53-mediated cell cycle arrest, despite radiation. We further show that the transcriptional regulation of cyclin D1 and cell cycle control by TFII-I are dependent on its tyrosine phosphorylation at positions 248 and 611, sites required for its growth signal-mediated transcriptional activity. Taken together, our data define TFII-I as a growth signal-dependent transcriptional activator that is critical for cell cycle control and proliferation and further reveal that genotoxic stress-induced degradation of TFII-I results in cell cycle arrest.

* Corresponding author. Mailing address: Department of Pathology, Tufts University School of Medicine, 150 Harrison Ave., Boston, MA 02111. Phone: (617) 636-6715. Fax: (617) 636-2990. E-mail: ananda.roy{at}tufts.edu.

Molecular and Cellular Biology, December 2005, p. 10940-10952, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.10940-10952.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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