Inhibition of cyclin D1 kinase activity is associated with E2F-mediated inhibition of cyclin D1 promoter activity through E2F and Sp1
- Author(s)
- Watanabe, G; Albanese, C; Lee, RJ; Reutens, A; Vairo, G; Henglein, B; Pestell, RG;
- Details
- Publication Year 1998-06,Volume 18,Issue #6,Page 3212-3222
- Journal Title
- MOLECULAR AND CELLULAR BIOLOGY
- Publication Type
- Journal Article
- Abstract
- 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 PRE 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.
- Publisher
- AMER SOC MICROBIOLOGY
- Keywords
- SUSCEPTIBILITY GENE-PRODUCT; TRANSCRIPTION FACTOR E2F; S-PHASE ENTRY; CELL-CYCLE; RETINOBLASTOMA PROTEIN; REGULATED TRANSCRIPTION; FUNCTIONAL INTERACTION; GROWTH SUPPRESSION; FIBROBLASTS LEADS; MAMMALIAN-CELLS
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Creation Date: 1998-06-01 12:00:00