Abstract
The cholesterol side-chain cleavage enzyme, cytochrome P450scc, initiates the biosynthesis of all steroid hormones. Adrenal and gonadal strategies for P450scc gene transcription are essentially identical and depend on the orphan nuclear receptor steroidogenic factor-1, but the placental strategy for transcription of P450scc employs cis-acting elements different from those used in the adrenal strategy and is independent of steroidogenic factor-1. Because placental expression of P450scc is required for human pregnancy, we sought factors that bind to the -155/-131 region of the human P450scc promoter, which participates in its placental but not adrenal or gonadal transcription. A yeast one-hybrid screen of 2.4 x 10(6) cDNA clones from human placental JEG-3 cells yielded two unique clones; one is the previously described transcription factor LBP-1b, which is induced by HIV, type I infection of lymphocytes, and the other is a new factor, termed LBP-9, that shares 83% amino acid sequence identity with LBP-1b. When expressed in transfected yeast, both factors bound specifically to the -155/-131 DNA; antisera to LBP proteins supershifted the LBP-9.DNA complex and inhibited formation of the LBP-1b.DNA complex. Reverse transcriptase-polymerase chain reaction detected LBP-1b in human placental JEG-3, adrenal NCI-H295A, liver HepG2, cervical HeLa, and monkey kidney COS-1 cells, but LBP-9 was detected only in JEG-3 cells. When the -155/-131 fragment was linked to a minimal promoter, co-expression of LBP-1b increased transcription 21-fold in a dose-dependent fashion, but addition of LBP-9 suppressed the stimulatory effect of LBP-1b. The roles of LBP transcription factors in normal human physiology have been unclear. Their modulation of placental but not adrenal P450scc transcription underscores the distinctiveness of placental strategies for steroidogenic enzyme gene transcription.
Highlights
Steroid hormones regulate a wide variety of physiologic functions
Such studies led to the discovery of steroidogenic factor-1 (SF-1),1 known as Ad4-BP, an orphan nuclear receptor that is essential for fetal adrenal and gonadal development as well as for expression of all the steroidogenic genes in these tissues [19]
As little is known about SF-1-independent expression of genes for steroidogenic enzymes, we have studied the transcription of P450scc in human placental JEG-3 cells [24, 25]
Summary
Steroid hormones regulate a wide variety of physiologic functions. Mineralocorticoids, produced by the adrenal cortex, are needed to retain sodium and maintain blood pressure [1]; glucocorticoids, produced by the adrenal cortex, raise blood sugar and play roles in numerous physiologic processes [2]; and androgens and estrogens, produced by the gonads, are required for reproduction [3, 4]. Because of its key role in the production of all steroid hormones, the transcription of the P450scc gene has been the subject of intensive study Such studies led to the discovery of steroidogenic factor-1 (SF-1), known as Ad4-BP, an orphan nuclear receptor that is essential for fetal adrenal and gonadal development as well as for expression of all the steroidogenic genes in these tissues [19]. As little is known about SF-1-independent expression of genes for steroidogenic enzymes, we have studied the transcription of P450scc in human placental JEG-3 cells [24, 25]. We report the cloning and characterization of two transcription factors that modulate the human placental expression of P450scc; both factors are related to the LBP-1 family of transcription factors induced by HIV, type I infection of lymphocytes [26]
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