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This version published online on March 27, 2003
Molecular Endocrinology, doi:10.1210/me.2002-0418
Molecular Endocrinology Vol. 0, No. 2003 200204181-
doi:10.1210/me.2002-0418
Copyright © 2003 by the Endocrine Society.
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Submitted on December 13, 2002
Accepted on March 20, 2003

Functional Cooperation between Multiple Regulatory Elements in the Untranslated Exon 1 Stimulates the Basal Transcription of the Human GnRH-II Gene

Chi Keung Cheng1, Ruby L. C. Hoo1, Billy K. C. Chow1, and Peter C. K. Leung1*

1 Department of Obstetrics and Gynecology, University of British Columbia (C. K. C., P. C. K. L.), Vancouver, Canada V6H 3V5; Department of Zoology, University of Hong Kong (R. L. C. H., B. K. C. C.), Hong Kong, China

* To whom correspondence should be addressed. E-mail: peleung{at}interchange.ubc.ca.

The wide distribution of GnRH-II and conservation of its structure over all vertebrate classes suggest that the neuropeptide possesses vital biological functions. Although recent studies have shown that the expression of the human GnRH-II gene is regulated by cAMP and estrogen, the molecular mechanisms governing its basal transcription remain poorly understood. Using the neuronal TE-671 and placental JEG-3 cells, we showed that the minimal human GnRH-II promoter was located between nucleotide (nt) -1124 and -750 (relative to the translation start codon) and that the untranslated exon 1 was important to produce full promoter activity. Two putative E-box binding sites (EBSs) and one Ets-like element (ELE) were identified within the first exon, and mutational analysis demonstrated that these cis-acting elements functioned cooperatively to stimulate the human GnRH-II gene transcription. EMSAs, UV cross-linking and Southwestern blot analyses indicated that the basic helix-loop-helix (bHLH) transcription factor AP-4 bound specifically to the two EBSs, whereas an unidentified protein bound to the ELE. The functional importance of AP-4 in controlling human GnRH-II gene transcription was demonstrated by over-expression of sense and anti-sense full-length AP-4 cDNAs. Taken together, our present data demonstrate a novel mechanism in stimulating basal human GnRH-II gene transcription mediated by cooperative actions of multiple regulatory elements within the untranslated first exon of the gene.
Key words: GnRH-II • promoter • transcriptional regulation • E-box • basic helix-loop-helix (bHLH) • AP-4 • Ets




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