Steroidogenic factor 1 (SF-1), an orphan member of the intracellular receptor superfamily, plays an essential role in the development and function of multiple endocrine organs. It is expressed in all steroidogenic tissues where it regulates the P450 steroidogenic genes to generate physiologically active steroids. Although many of the functions of SF-1 in vivo have been defined, an unresolved question is whether a ligand modulates its transcriptional activity. Here, we show that 25-, 26-, or 27-hydroxycholesterol, known suppressors of cholesterol biosynthesis, enhance SF-1-dependent transcriptional activity. This activation is dependent upon the SF-1 activation function domain, and, is specific for SF-1 as several other receptors do not respond to these molecules. The oxysterols activate at concentrations comparable to those previously shown to inhibit cholesterol biosynthesis, and, can be derived from cholesterol by P450c27, an enzyme expressed within steroidogenic tissues. Recent studies have shown that the nuclear receptor LXR also is activated by oxysterols. We demonstrate that different oxysterols differ in their rank order potency for these two receptors, with 25-hydroxycholesterol preferentially activating SF-1 and 22(R)-hydroxycholesterol preferentially activating LXR. These results suggest that specific oxysterols may mediate transcriptional activation via different intracellular receptors. Finally, ligand-dependent transactivation of SF-1 by oxysterols may play an important role in enhancing steroidogenesis in vivo.Steroidogenic factor 1 (SF-1), a monomer member of the orphan nuclear receptor family, is expressed from the inception of adrenal and gonadal development, and mice deficient in SF-1 lack these organs (1-4). SF-1 also plays an important role in regulating the expression of multiple components of steroidogenesis, including the cytochrome P450 steroid hydroxylases and the steroidogenic acute regulatory protein (5, 6). Finally, SF-1 is important for the expression of several key products of pituitary gonadotropes, including folliclestimulating hormone, leutinizing hormone, and the receptor for gonadotropin-releasing hormone (7). These results have established a critical role for SF-1 at multiple levels of endocrine development and function. An unresolved question, however, has been whether SF-1-dependent transcriptional activity is modulated by a ligand-either endogenous to steroidogenic cells or supplied in an endocrine fashion. In the present study, we have begun to answer this question by examining several different steroidogenic intermediates or their derivatives for their ability to activate SF-1. Our results demonstrate that certain endogenous oxysterols such as 25-, 26-, or 27-hydroxycholesterol (OHC), known inhibitors of cholesterol biosynthesis (8, 9), selectively enhance SF-1 mediated transcriptional activity. These compounds may be generated in vivo through the actions of the enzyme P450c27 (10-12). Furthermore, activation by these molecules is observed at concentrations compar...

T-cell hybridomas, thymocytes, and T cells can be induced to undergo apoptotic cell death by activation through the T-cell receptor. This process requires macromolecular synthesis and thus gene expression, and it has been shown to be influenced by factors regulating transcription. Recently, activation, T-cell hybridomas rapidly express the Fas/CD95 receptor and its ligand, Fas ligand (FasL), which interact to transduce the death signal in the activated cell. Retinoids, the active metabolites of vitamin A, modulate expression of specific target genes by binding to two classes of intracellular receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). They are potent modulators of apoptosis in a number of experimental models, and they have been shown to inhibit activation-induced apoptosis in T-cell hybridomas and thymocytes. Particularly effective is the prototypic pan-agonist 9-cis retinoic acid (9-cis RA), which has high affinity for both RARs and RXRs. We report here that 9-cis RA inhibits T-cell receptor-mediated apoptosis in T-cell hybridomas by blocking the expression of Fas ligand following activation. This inhibition appears to be at the level of FasL mRNA, with the subsequent failure to express cell surface FasL. RAR-selective (TTNPB) or RXR-selective (LG100268) ligands alone were considerably less potent than RAR-RXR pan-agonists. However, the addition of both RAR- and RXR-selective ligands was as effective as the addition of 9-cis RA alone. The demonstrates that the inhibitory effect requires the ligand-mediated activation of both retinoid receptor signaling pathways.