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Molecular and Cellular Biology, September 2005, p. 8037-8043, Vol. 25, No. 18
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.18.8037-8043.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Function of AP-1 in Transcription of the Telomerase Reverse Transcriptase Gene (TERT) in Human and Mouse Cells

Masahiro Takakura,1,2 Satoru Kyo,2 Masaki Inoue,2 Woodring E. Wright,1 and Jerry W. Shay1*

Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9039,1 Department of Obstetrics and Gynecology, Kanazawa University, School of Medicine, Kanazawa, Ishikawa 920-8641, Japan2

Received 12 April 2005/ Returned for modification 3 May 2005/ Accepted 5 July 2005

The transcriptional regulation of the human telomerase catalytic subunit (hTERT) plays a critical role in telomerase activity. Approximately 200 bp of the proximal core promoter is responsible for basic hTERT expression; however, the function of the distal regulatory elements remains unclear. The transcription factor activator protein 1 (AP-1) is involved in cellular proliferation, differentiation, carcinogenesis, and apoptosis and is expressed broadly in both cancer and normal cells. There are several putative AP-1 sites in the hTERT promoter, but their functions are unknown. The present study examined the regulatory role of AP-1 in hTERT gene transcription. Overexpression of AP-1 leads to transcriptional suppression of hTERT in cancer cells. The combination of c-Fos and c-Jun or c-Fos and JunD strongly suppresses hTERT promoter activity in transient-expression analyses. The hTERT promoter region between –2000 and –378 is responsible for this function. Gel shift and supershift analyses, as well as ChIP, show binding of JunD and c-Jun on two putative AP-1 sites within this region. Mutations in the AP-1 binding sites rescued suppressions caused by AP-1, suggesting this is a direct regulation of the hTERT promoter. In contrast, there was no effect on mTERT expression or mTERT promoter activity by AP-1 overexpression in mouse fibroblasts. The species-specific function of AP-1 in TERT expression may in part help explain the difference in telomerase activity between normal human and mouse cells.

* Corresponding author. Mailing address: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9039. Phone: (214) 648-3282. Fax: (214) 648-8694. E-mail: jerry.shay{at}utsouthwestern.edu.

Molecular and Cellular Biology, September 2005, p. 8037-8043, Vol. 25, No. 18
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.18.8037-8043.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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