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Molecular and Cellular Biology, March 2000, p. 2014-2022, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Pocket Protein-Independent Repression of Urokinase-Type Plasminogen Activator and Plasminogen Activator Inhibitor 1 Gene Expression by E2F1

Magdalena Koziczak, Wilhelm Krek, and Yoshikuni Nagamine*

Friedrich Miescher Institute, Basel, Switzerland

Received 21 July 1999/Returned for modification 20 September 1999/Accepted 22 December 1999

Expression of genes of the plasminogen activator (PA) system declines at the G0/G1-S-phase boundary of the cell cycle. We found that overexpression of E2F1-3, which acts mainly in late G1, inhibits promoter activity and endogenous expression of the urokinase-type PA (uPA) and PA inhibitor 1 (PAI-1) genes. This effect is dose dependent and conserved in evolution. Mutation analysis indicated that both the DNA-binding and transactivation domains of E2F1 are necessary for this regulation. Interestingly, an E2F1 mutant lacking the pRB-binding region strongly repressed the uPA and PAI-1 promoters. An E2F-mediated negative effect was also observed in pRB and p107/p130 knockout cell lines. This is the first report that E2F can act as a repressor independently of pocket proteins. Mutation of AP-1 elements in the uPA promoter abrogated E2F-mediated transcriptional inhibition, suggesting the involvement of AP-1 in this regulation. Results shown here identify E2F as an important component of transcriptional control of the PA system and thus provide new insights into mechanisms of cellular proliferation.

* Corresponding author. Mailing address: Friedrich Miescher Institute, P.O. Box 2543, CH-4002 Basel, Switzerland. Phone: 41-61-6976669. Fax: 41-61-6973976 or 1-815-327-0931. E-mail: nagamine{at}fmi.ch.

Molecular and Cellular Biology, March 2000, p. 2014-2022, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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