Function of AP-1 in transcription of the telomerase reverse transcriptase gene (TERT) in human and mouse cells.
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.
Takakura
Masahiro
M
Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9039, USA.
Kyo
Satoru
S
Inoue
Masaki
M
Wright
Woodring E
WE
Shay
Jerry W
JW
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse