2 DISTINCT MECHANISMS ELICIT ANDROGEN-DEPENDENT EXPRESSION OF THE MOUSE SEX-LIMITED PROTEIN GENE

The mouse sex-limited protein (Slp) gene is expressed in liver and kid ney of adult males and is testosterone-inducible in females, indicativ e of androgen dependence. Analysis of mRNA levels and chromatin config uration reveals that this androgen regulation is achieved by distinct means in the two tissues. In the liver, Slp expression requires pituit ary function, and specifically, as shown by others, a pulsatile patter n of GH secretion that is itself determined by androgen. After hypophy sectomy, slp synthesis cannot be reestablished in liver by testosteron e, although mRNA decline can be slowed. In contrast, in the kidney Slp mRNA is directly induced by androgen in hypophysectomized mice. In vi vo footprinting was used to examine the role of the Slp enhancer, whic h directs androgen-specific transcription in transfection and contains a factor-binding site, FPIV, whose protection in vivo has been correl ated with Slp expression. In kidney, FPIV was protected in intact male s and hypophysectomized mice supplemented with testosterone, but not i n females or untreated hypophysectomized mice, corroborating FPIV's as sociation with androgen-driven transcription. Surprisingly, protection of FPIV also occurred in liver of hypophysectomized males treated wit h testosterone, despite the lack of Slp expression. Thus androgen dire ctly affects the Slp enhancer in kidney, where steroid is sufficient f or gene activation, as well as in liver, where chromatin remodeling oc curs in response to androgen, although GH is clearly required for expr ession. This may indicate that both GH and androgen signal transductio n pathways target the Slp enhancer to elicit precise gene regulation.