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Translin Coactivates Steroidogenic Factor-1-Stimulated Transcription

Department of Obstetrics, Gynecology, and Reproductive Sciences (S.H.M., S.R.B., C.D., J.-L.V., P.B.B.), The Center for Reproductive Sciences, University of California, San Francisco, California 94143; and Department of Obstetrics and Gynecology, and Center for Research on Reproduction and Women’s Health (N.B.H.), University of Pennsylvania, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Synthia H. Mellon, Ph.D., Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, 513 Parnassus Avenue, Box 0556, San Francisco, California 94143-0556. E-mail: mellon{at}cgl.ucsf.edu.

Transcription of the rat P450c17 gene in Leydig cells requires steroidogenic factor-1 (SF-1) (NR5A1), nerve growth factor-inducible protein B (nurr77), COUP-TF, and SET. The –447/–419 region of this promoter contains two binding sites for orphan nuclear receptors that are required for activation by SF-1, nerve growth factor-inducible protein B, and cAMP. We identified a novel factor, steroidogenic factor-inducer of transcription-2, that binds to this –447/–419 region. We have now purified steroidogenic factor-inducer of transcription-2 from mouse Leydig MA-10 cells and identified it by mass spectrometry as translin, a 27-kDa protein that exerts many functions. By itself, translin cannot activate a P450c17-promoter/reporter construct in HeLa cells; however, translin increased SF-1-stimulated transcription 2-fold, indicating cooperativity between SF-1 and translin. Mutation of both SF-1 binding sites in the –447/–419 sequence eliminated activation by SF-1 and translin. Translin did not augment SF-1-stimulated transcription from all SF-1-responsive elements, suggesting that the activation is specific for the sequence of the SF-1 response element. Gel shift analysis of double- and single-stranded DNA showed that translin binds to single-stranded DNA, but its transcriptional activation is independent of DNA binding. The hinge region of SF-1 is necessary for activation by translin; deletion of hinge amino acids 170–225 in SF-1 eliminates translin’s ability to augment SF-1-dependent transcription. A translin-like protein, called translin-associated factor X, can substitute for a translin moiety; translin homomers and translin/translin-associated factor X heteromers activated SF-1-stimulated transcription equally. Thus, we have identified a new factor that works together with SF-1 to augment gene transcription in a DNA-specific fashion.

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Nuclear Receptors:   SF-1

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