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Mol Cell Biol, June 1998, p. 3212-3222, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Inhibition of Cyclin D1 Kinase Activity Is Associated with E2F-Mediated Inhibition of Cyclin D1 Promoter Activity through E2F and Sp1

Genichi Watanabe,1 Chris Albanese,1 Richard J. Lee,1 Anne Reutens,1 Gino Vairo,2 Berthold Henglein,3 and Richard G. Pestell1,*

Albert Einstein Cancer Center, Department of Medicine and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 104611; Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Melbourne, Victoria, 3050, Australia2; and Institut Curie, INSERM U 255, F-75005 Paris, France3

Received 17 September 1997/Returned for modification 12 November 1997/Accepted 6 March 1998

Coordinated interactions between cyclin-dependent kinases (Cdks), their target "pocket proteins" (the retinoblastoma protein [pRB], p107, and p130), the pocket protein binding E2F-DP complexes, and the Cdk inhibitors regulate orderly cell cycle progression. The cyclin D1 gene encodes a regulatory subunit of the Cdk holoenzymes, which phosphorylate the tumor suppressor pRB, leading to the release of free E2F-1. Overexpression of E2F-1 can induce apoptosis and may either promote or inhibit cellular proliferation, depending upon the cell type. In these studies overexpression of E2F-1 inhibited cyclin D1-dependent kinase activity, cyclin D1 protein levels, and promoter activity. The DNA binding domain, the pRB pocket binding region, and the amino-terminal Sp1 binding domain of E2F-1 were required for full repression of cyclin D1. Overexpression of pRB activated the cyclin D1 promoter, and a dominant interfering pRB mutant was defective in cyclin D1 promoter activation. Two regions of the cyclin D1 promoter were required for full E2F-1-dependent repression. The region proximal to the transcription initiation site at -127 bound Sp1, Sp3, and Sp4, and the distal region at -143 bound E2F-4-DP-1-p107. In contrast with E2F-1, E2F-4 induced cyclin D1 promoter activity. Differential regulation of the cyclin D1 promoter by E2F-1 and E2F-4 suggests that E2Fs may serve distinguishable functions during cell cycle progression. Inhibition of cyclin D1 abundance by E2F-1 may contribute to an autoregulatory feedback loop to reduce pRB phosphorylation and E2F-1 levels in the cell.

* Corresponding author. Mailing address: The Albert Einstein Cancer Center, Department of Medicine and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Chanin 302B, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-8662. Fax: (718) 430-8674. E-mail: pestell{at}aecom.yu.edu.

Mol Cell Biol, June 1998, p. 3212-3222, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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