Gonadotropin-releasing hormone activation of c-jun, but not early growth response factor-1, stimulates transcription of a luteinizing hormone beta-subunit gene.
Transcription of mammalian LH beta-subunit genes (LHbeta) 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 LHbeta 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 LHbeta (csLHbeta) gene is also unresponsive to Egr-1. The homologous LHbeta promoters in other fish contain a conserved estrogen response element-like sequence, which we recently demonstrated is not required for estrogen receptor (ER) alpha association with the csLHbeta 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 csLHbeta 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 ERalpha and exerts synergistic effects on promoter activity with Sf-1, ERalpha, 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 LHbeta 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.[1]References
- Gonadotropin-releasing hormone activation of c-jun, but not early growth response factor-1, stimulates transcription of a luteinizing hormone beta-subunit gene. Melamed, P., Zhu, Y., Tan, S.H., Xie, M., Koh, M. Endocrinology (2006) [Pubmed]
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