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Molecular and Cellular Biology, November 1998, p. 6191-6200, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Sp1-Mediated Transcription of the Werner Helicase Gene Is Modulated by Rb and p53

Yukako Yamabe,1 Akira Shimamoto,1 Makoto Goto,2 Jun Yokota,3 Minoru Sugawara,1 and Yasuhiro Furuichi1,*

AGENE Research Institute, Kamakura, Kanagawa 247,1 Tokyo Metropolitan Otsuka Hospital, Minami Otsuka, Toshima-ku, Tokyo 170,2 and National Cancer Center, Chuo-ku, Tokyo 104,3 Japan

Received 3 April 1998/Returned for modification 23 June 1998/Accepted 12 August 1998

The regulation of Werner's syndrome gene (WRN) expression was studied by characterizing the cis-regulatory elements in the promoter region and the trans-activating factors that bind to them. First, we defined the transcription initiation sites and the sequence of the 5' upstream region (2.8 kb) of WRN that contains a number of cis-regulatory elements, including 7 Sp1, 9 retinoblastoma control element (RCE), and 14 AP2 motifs. A region consisting of nucleotides -67 to +160 was identified as the principal promoter of WRN by reporter gene assays in HeLa cells, using a series of WRN promoter-luciferase reporter (WRN-Luc) plasmids that contained the 5'-truncated or mutated WRN upstream regions. In particular, two Sp1 elements proximal to the transcription initiation site are indispensable for WRN promoter activity and bind specifically to Sp1 proteins. The RCE enhances WRN promoter activity. Coexpression of the WRN-Luc plasmids with various dosages of plasmids expressing Rb or p53 in Saos2 cells lacking active Rb and p53 proteins showed that the introduced Rb upregulates WRN promoter activity a maximum of 2.5-fold, while p53 downregulates it a maximum of 7-fold, both dose dependently. Consistently, the overexpressed Rb and p53 proteins also affected the endogenous WRN mRNA levels in Saos2 cells, resulting in an increase with Rb and a decrease with p53. These findings suggest that WRN expression, like that of other housekeeping genes, is directed mainly by the Sp1 transcriptional control system but is also further modulated by transcription factors, including Rb and p53, that are implicated in the cell cycle, cell senescence, and genomic instability.

* Corresponding author. Mailing address: AGENE Research Institute, 200 Kajiwara, Kamakura, Kanagawa 247, Japan. Phone: 81-467-46-9590. Fax: 81-467-48-6595. E-mail: furuichi{at}agene.co.jp.

Molecular and Cellular Biology, November 1998, p. 6191-6200, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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