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Small Nuclear RING Finger Protein Stimulates the Rat Luteinizing Hormone-ß Promoter by Interacting with Sp1 and Steroidogenic Factor-1 and Protects from Androgen Suppression

Departments of Pharmacology (D.C.), Physiology (H.A.F.), and Internal Medicine (M.G., M.A.S.), University of Virginia, Charlottesville, Virginia 22908; and Institute of Biomedicine (M.H., O.A.J., J.J.P.) and Department of Clinical Chemistry (O.A.J.), University of Helsinki and Helsinki University Central Hospital, FIN-00014 Helsinki, Finland

Address all correspondence and requests for reprints to: Margaret A. Shupnik, Ph.D, Department of Internal Medicine/Endocrinology, PO Box 800578 Health Sciences Center, University of Virginia, Charlottesville, Virginia 22908. E-mail: mas3x{at}virginia.edu.

GnRH controls expression of the LH subunit genes, and LHß, with the LHß subunit regulated most dramatically. Two enhancer regions, distal and proximal, on the rat LHß gene promoter cooperate for full basal expression and GnRH stimulation. It has been hypothesized that the transcription factors binding to these regions, Sp1, Egr-1, and steroidogenic factor 1 (SF-1), may interact directly or indirectly via a coactivator. One such coactivator may be small nuclear RING finger protein (SNURF), which is expressed in pituitary tissue and the LßT2 gonadotrope cell line. In transfection experiments in LßT2 cells, SNURF stimulated basal expression of LHß and increased overall GnRH stimulation. SNURF specifically stimulated LHß, with no effect on the -subunit promoter. SNURF interacts with Sp1 and SF-1, but not Egr-1, in pull-down experiments. Point mutations or deletions of SNURF functional domains demonstrated that Sp1 and SF-1 interactions with SNURF are required for SNURF stimulatory effects on the LHß promoter. Endogenous SNURF is associated with the LHß promoter on native chromatin, suggesting that it plays a physiological role in LHß gene expression. SNURF also binds the androgen receptor, and SNURF overexpression overcomes androgen suppression of GnRH-stimulated LHß but not subunit promoter activity. SNURF mutations that disrupt Sp1 or SF-1 binding eliminate rescue by SNURF. We conclude that SNURF may mediate interactions between the distal and proximal GnRH response regions of the LHß promoter to stimulate transcription and can also protect the promoter from androgen suppression.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR  |  SF-1

Coregulators:   SNURF  |  CBP  |  p300

Ligands:   Dihydrotestosterone

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