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Mol Cell Biol, June 1998, p. 3212-3222, Vol. 18, No. 6
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
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
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.
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