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Molecular Endocrinology 11 (7): 891-904
Copyright © 1997 by The Endocrine Society

Multiple Orphan Nuclear Receptors Converge to Regulate Rat P450c17 Gene Transcription: Novel Mechanisms for Orphan Nuclear Receptor Action

Peilin Zhang and Synthia H. Mellon

Department of Obstetrics, Gynecology, and Reproductive Sciences (P.Z.)and The Metabolic Research Unit (S.H.M.), University of California, San Francisco, California 94143-0556

The orphan nuclear receptor steroidogenic factor-1 (SF-1) plays a key role in regulating the expression of the rat P450c17 gene in testicular Leydig and in adrenocortical cells. Other DNA sequences, not bound by SF-1, are also involved in transcriptional regulation of the rat P450c17 gene in both cell types. The region from -447/-399 or from -447/-419 increased both basal and cAMP-induced transcription, and the region from -418/-399 increased basal transcription to a greater extent than the intact -447/-399 DNA. The -447/-399 DNA sequence contains three imperfect copies of the orphan nuclear receptor-binding motif, AGGTCA, and at least three known orphan nuclear receptors, chicken ovalbumin upstream promoter transcription factor (COUP-TF), SF-1, and an early response gene induced by nerve growth factor (NGFI-B), bind to -447/-399 DNA. The AGGTCA triad is bound by one set of nuclear proteins when these three elements are colinear and is bound by a different set of proteins when these elements are separated. When the elements are separated, COUP-TF no longer binds, and the region -418/-399 is bound by a protein that greatly stimulates basal transcription. The region -447/-419 is bound by two different proteins that mediate both basal and cAMP-stimulated transcription. We call the protein binding to -418/-399 steroidogenic factor inducer of transcription-1 (StF-IT-1), and one of the proteins binding to -447/-419, StF-IT-2. SF-1 binds to a second AGGTCA element in the -447/-419 region. StF-IT-1 and StF-IT-2 are both found in Leydig and adrenal cells, and transcriptional regulation is similar in both cell types. SF-1 and NGF-IB may increase transcription by displacing COUP-TF (a transcriptional repressor) because these proteins share DNA-binding domains. However, neither SF-1 nor NGF-IB alone, binding as monomers, increases transcription. Rather, these proteins must interact with another DNA-binding protein, e.g. StF-IT-2, to increase transcription. StF-IT-2 also requires interaction with SF-1 (or NGF-IB) bound to DNA and cannot increase transcription by itself. This mechanism of action is different from the mechanism by which SF-1 regulates transcription from the -84/-55 region of the rat P450c17 gene. Thus, we have defined a novel mechanism of action for orphan nuclear receptors that bind to DNA as monomers.




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