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Gonadotropin-Releasing Hormone Activation of C-jun, But Not Early Growth Response Factor-1, Stimulates Transcription of a Luteinizing Hormone ß-Subunit Gene

Department of Biological Sciences, National University of Singapore, Singapore 117542

Address all correspondence and requests for reprints to: Philippa Melamed, Functional Genomics Laboratories, Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117542. E-mail: dbsmp{at}nus.edu.sg.

Transcription of mammalian LH ß-subunit genes (LHß) is regulated by GnRH through activation of early growth response factor-1 (Egr-1), which interacts synergistically with steroidogenic factor-1 (Sf-1) and pituitary homeobox-1 (Pitx1) at the promoter; Egr-1 is thought to comprise the major mediator of this effect. However, the proximal promoters of LHß genes in lower vertebrates lack an Egr-1 response element yet are responsive to GnRH; we demonstrate here that the promoter of the Chinook salmon LHß (csLHß) gene is also unresponsive to Egr-1. The homologous LHß promoters in other fish contain a conserved estrogen response element-like sequence, which we recently demonstrated is not required for estrogen receptor (ER) association with the csLHß gene. Here we show that the estrogen response element-like element is required for the GnRH effect and for a response to c-jun overexpression. Using plasmid immunoprecipitation, we show that after GnRH exposure, c-jun associates with the intact csLHß gene promoter through this element. We further show that the effect of c-jun requires its DNA-binding domain and that c-jun interacts with Sf-1 and ER and exerts synergistic effects on promoter activity with Sf-1, ER, and Pitx1. Finally, we demonstrate the role of c-jun in mediating the GnRH effect on this gene through knockdown of c-jun expression or use of a dominant negative. We conclude that c-jun mediation of the GnRH effect on the LHß gene may be common in lower vertebrates and may have preceded an evolutionary divergence in the cis-regulatory elements that led to its function being replaced in mammals by Egr-1.

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