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Type: Journal article
Title: Differentiation-specific action of orphan nuclear receptor NR5A1 (SF-1): transcriptional regulation in luteinizing bovine theca cells
Author: Walther, N.
Jansen, M.
Akbary, W.
Ivell, R.
Citation: Reproductive Biology and Endocrinology, 2006; 4(1):1-15
Publisher: Biomed Central Ltd.
Issue Date: 2006
ISSN: 1477-7827
Statement of
Norbert Walther, Martina Jansen, Wasima Akbary and Richard Ivell
Abstract: BACKGROUND: The orphan nuclear receptor NR5A1 (steroidogenic factor-1, SF-1) is a master regulator of tissue-specific gene expression in reproductive and steroidogenic tissues. Two activating functions, AF-1 and AF-2, have been described to function in a cooperative manner to recruit transcriptional coactivators to the promoter regions of NR5A1-controlled genes. METHODS: The role of the NR5A1 activating functions AF-1 and AF-2 was studied in primary bovine theca cells. Bovine theca cells were infected with recombinant adenovirus vectors over-expressing wild-type NR5A1 or NR5A1 mutants, in which one of the activating functions of this orphan nuclear receptor had been impaired. Under different culture conditions, theca cell-specific transcript levels were measured by reverse transcription and real-time PCR. RESULTS: Under culture conditions optimized for cell growth, transcriptional up-regulation of CYP11A1 (P450 side chain-cleavage enzyme) and INSL3 (Insulin-like factor 3, Relaxin-like factor (RLF)) was found to be dependent on the presence of NR5A1 carrying an intact AF-2. Under conditions inducing luteal differentiation of theca cells, CYP11A1 and STAR (Steroidogenic acute regulatory protein) were up-regulated by the action of luteinizing hormone (LH), whereas the differentiation-specific up-regulation of INSL3 was suppressed by LH in luteinizing theca cells. Inhibition of insulin- or IGF1- (insulin-like growth factor I) dependent signal transduction by the RAF1 kinase inhibitor GW5074 and the mitogen-activated protein kinase kinase inhibitor PD98059 resulted in the finding that RAF1 kinase inhibition was able to counteract the LH-dependent regulation of NR5A1-controlled genes, whereas inhibition of the mitogen-activated protein kinase (MAP kinase) pathway did not have any significant effect. CONCLUSION: The regulation of the three NR5A1-controlled genes CYPA11, STAR, and INSL3 in luteinizing theca cells apparently is not dependent on NR5A1 activating functions AF-1 or AF-2. Activation of AF-1 here even appears to have an impairing effect on NR5A1 transcriptional activity, implying that up-regulation of NR5A1-controlled genes uses a different pathway. Our results might be explained by the possible existence of an interconnection between the RAF1 kinase and the cyclic AMP-protein kinase A pathway. Such a non-classical regulatory pathway might play an important role in the control of gene expression in reproductive and steroidogenic tissues.
Keywords: Theca Cells
Cells, Cultured
Luteinizing Hormone
Peptide Hormones
Cholesterol Side-Chain Cleavage Enzyme
Proto-Oncogene Proteins c-raf
Carrier Proteins
Receptors, Cytoplasmic and Nuclear
Recombinant Fusion Proteins
Transcription Factors
Cyclic AMP
Transduction, Genetic
Cell Differentiation
MAP Kinase Signaling System
Second Messenger Systems
Transcription, Genetic
Gene Expression Regulation
Protein Processing, Post-Translational
Protein Structure, Tertiary
Rights: © 2006 Walther et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI: 10.1186/1477-7827-4-64
Published version:
Appears in Collections:Aurora harvest 6
Molecular and Biomedical Science publications

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