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Mol. Hum. Reprod. Advance Access originally published online on December 22, 2008
Molecular Human Reproduction 2009 15(2):77-87; doi:10.1093/molehr/gan079
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Conservation of mechanisms mediating gonadotrophin-releasing hormone 1 stimulation of human luteinizing hormone β subunit transcription

Jérôme Fortin, Pankaj Lamba, Ying Wang and Daniel J. Bernard1

Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Sciences Building, 3655 Promenade Sir-William-Osler Montréal, QC, Canada H3G 1Y6

1 Correspondence address. Tel: +1-514-398-2525; Fax: +1-514-398-6705; E-mail: daniel.bernard{at}mcgill.ca

Gonadotrophin-releasing hormone (GNRH1) regulates pituitary luteinizing hormone (LH). Previous studies have delineated a mechanism for GNRH1-induced LHβ subunit gene (Lhb) transcription, the rate-limiting step in LH production. GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. Though the cis-elements for these factors are conserved across species, regulation of human LHB transcription has not been thoroughly investigated. We therefore characterized LHB transcriptional regulation by GNRH1 using promoter-reporter analyses in LβT2 cells. GNRH1 stimulated LHB transcription via an extracellular signal-regulated kinase 1/2 pathway. EGR1 bound to two binding sites on the LHB promoter and this binding was increased by GNRH1. Mutation of either site or knockdown of endogenous EGR1 decreased basal and/or GNRH1-regulated promoter activity. The human LHB promoter also contains low and high affinity SF1 binding sites. Mutation of these elements or depletion of endogenous SF1 impaired basal and ligand-induced transcription. Knockdown of PITX1 or PITX2 isoforms impaired GNRH1 induction, and endogenous PITX1 bound to the candidate PITX binding site on the LHB promoter. Thus, the mechanism described for GNRH1 regulation of Lhb in other species is largely conserved for human LHB. We also uncover a previously unappreciated role for PITX2 isoforms in this process.

Key words: gonadotrophin/pituitary/EGR1/SF1/PITX

Submitted on October 22, 2008; resubmitted on December 9, 2008; accepted on December 17, 2008.


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