Species differences in GnRH activation of the LHbeta promoter: role of Egr1 and Sp1.
Abstract: Activation of the luteinizing hormone beta (LHbeta) promoter by gonadotropin-releasing hormone (GnRH) via the transcription factor early growth response protein-1 (Egr1) has been well characterized. To determine the mechanisms affecting Egr1 regulation of LHbeta, we analyzed five different species of LHbeta promoters (equine, mouse, rat, bovine and human). Electrophoretic mobility shift assays (EMSAs) identified multiple transcription factors binding to the Egr regions on the LHbeta promoter. Species-specific differences existed in the binding affinity for Sp1, Sp3, steroidogenic factor-1 (SF-1) and Egr1. Upon mutation of the Egr elements, competition for the binding of all zinc finger proteins was lost, suggesting that the Sp proteins compete for binding to the same site that Egr1 occupies. In addition, the promoters from species that had the highest affinity for Sp1 also had the lowest activation by Egr1 and GnRH. Thus we hypothesize that Sp1 competes for Egr1 binding to the Egr elements on the LHbeta promoter and thus inhibits the ability of GnRH and Egr1 to activate the LHbeta promoter.
Publication Date: 2002-06-01 PubMed ID: 12039067DOI: 10.1016/s0303-7207(01)00744-4Google Scholar: Lookup
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- Journal Article
- Research Support
- U.S. Gov't
- P.H.S.
Summary
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This research article explores how gonadotropin-releasing hormone (GnRH) activates the luteinizing hormone beta (LHβ) promoter in various species, focusing on the role of the transcription factor early growth response protein-1 (Egr1) as well as other proteins such as Sp1. The study offers insights into species-specific differences and proposes that Sp1 competes for Egr1 binding, potentially inhibiting the activation of the LHβ promoter.
Understanding the Mechanism of Action
The research investigates how the GnRH activates the LHβ promoter, with a focus on the transcription factor Egr1. The process is facilitated by:
- Analyzing the LHβ promoters from five species: equine, mouse, rat, bovine and human.
- Application of electrophoretic mobility shift assays (EMSAs), a method for studying protein-DNA interaction, to identify various transcription factors binding to the Egr regions on the LHβ promoter.
Species-Specific Differences
The article reveals species-specific differences related to the binding affinity for Sp1, Sp3, steroidogenic factor-1 (SF-1), and Egr1 transcription factors. This includes:
- Identification of differing binding affinities for the transcription factors among the five species studied.
- The observation that mutation of Egr elements resulted in loss of competition for the binding of all zinc finger proteins. This suggests that the Sp proteins were competing for binding to the site previously occupied by Egr1.
The Role of Sp1 Protein
Sp1 is a transcription factor that binds to GC-rich DNA sequences. According to the research, Sp1 was found to compete with Egr1 for binding to the Egr elements on the LHβ promoter. This interaction was observed to have potential implications, including:
- The observed correlation between higher affinity for Sp1 and lower activation by Egr1 and GnRH in the species’ promoters.
- The hypothesis that Sp1 competes for Egr1 binding, thus inhibiting the ability of GnRH and Egr1 to activate the LHβ promoter.
In essence, these findings provide a potentially significant biological insight into the regulation of the LHβ promoter by GnRH, suggesting competition between transcription factors that could influence hormonal activation.
Cite This Article
APA
Call GB, Wolfe MW.
(2002).
Species differences in GnRH activation of the LHbeta promoter: role of Egr1 and Sp1.
Mol Cell Endocrinol, 189(1-2), 85-96.
https://doi.org/10.1016/s0303-7207(01)00744-4 Publication
Researcher Affiliations
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160-7401, USA.
MeSH Terms
- Animals
- Base Sequence
- Cell Line
- DNA-Binding Proteins / metabolism
- Early Growth Response Protein 1
- Genes, Reporter
- Gonadotropin-Releasing Hormone / metabolism
- Humans
- Immediate-Early Proteins
- Mice
- Molecular Sequence Data
- Promoter Regions, Genetic
- Sequence Alignment
- Sp1 Transcription Factor / metabolism
- Steroidogenic Factor 1
- Transcription Factors / metabolism
- Zinc Fingers
Grant Funding
- R29 DK50668 / NIDDK NIH HHS
- U54 HD33994 / NICHD NIH HHS
Citations
This article has been cited 10 times.- Wan Z, Yang H, Cai Y, Ma J, Cheng P, Wang Z, Wang F, Zhang Y. Comparative Transcriptomic Analysis of Hu Sheep Pituitary Gland Prolificacy at the Follicular and Luteal Phases.. Genes (Basel) 2022 Feb 27;13(3).
- Rudnizky S, Khamis H, Malik O, Squires AH, Meller A, Melamed P, Kaplan A. Single-molecule DNA unzipping reveals asymmetric modulation of a transcription factor by its binding site sequence and context.. Nucleic Acids Res 2018 Feb 16;46(3):1513-1524.
- Bagchi D, Andrade J, Shupnik MA. A new role for wilms tumor protein 1: differential activities of + KTS and -KTS variants to regulate LHβ transcription.. PLoS One 2015;10(1):e0116825.
- Burger LL, Haisenleder DJ, Marshall JC. GnRH pulse frequency differentially regulates steroidogenic factor 1 (SF1), dosage-sensitive sex reversal-AHC critical region on the X chromosome gene 1 (DAX1), and serum response factor (SRF): potential mechanism for GnRH pulse frequency regulation of LH beta transcription in the rat.. Endocrine 2011 Jun;39(3):212-9.
- Burger LL, Haisenleder DJ, Aylor KW, Marshall JC. Regulation of Lhb and Egr1 gene expression by GNRH pulses in rat pituitaries is both c-Jun N-terminal kinase (JNK)- and extracellular signal-regulated kinase (ERK)-dependent.. Biol Reprod 2009 Dec;81(6):1206-15.
- Fortin J, Lamba P, Wang Y, Bernard DJ. Conservation of mechanisms mediating gonadotrophin-releasing hormone 1 stimulation of human luteinizing hormone beta subunit transcription.. Mol Hum Reprod 2009 Feb;15(2):77-87.
- Walsh HE, Shupnik MA. Proteasome regulation of dynamic transcription factor occupancy on the GnRH-stimulated luteinizing hormone beta-subunit promoter.. Mol Endocrinol 2009 Feb;23(2):237-50.
- Salisbury TB, Binder AK, Nilson JH. Welcoming beta-catenin to the gonadotropin-releasing hormone transcriptional network in gonadotropes.. Mol Endocrinol 2008 Jun;22(6):1295-303.
- Maudsley S, Naor Z, Bonfil D, Davidson L, Karali D, Pawson AJ, Larder R, Pope C, Nelson N, Millar RP, Brown P. Proline-rich tyrosine kinase 2 mediates gonadotropin-releasing hormone signaling to a specific extracellularly regulated kinase-sensitive transcriptional locus in the luteinizing hormone beta-subunit gene.. Mol Endocrinol 2007 May;21(5):1216-33.
- Prandini MH, Dreher I, Bouillot S, Benkerri S, Moll T, Huber P. The human VE-cadherin promoter is subjected to organ-specific regulation and is activated in tumour angiogenesis.. Oncogene 2005 Apr 21;24(18):2992-3001.
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