Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital adrenal hyperplasia (CAH) comprises a family of inherited human disorders caused by a defect in cortisol biosynthesis. We previously reported absent cholesterol side-chain cleavage enzyme cytochrome P450 (P450scc) expression in rabbits affected with CAH. Further molecular studies via Southern blotting analyses, using a full-length human P450scc cDNA probe and a cloned rabbit P450scc cDNA probe, demonstrated the absence of P450scc DNA fragments in CAH animals. Reverse transcriptase-based polymerase chain reactions revealed that P450scc mRNA was not detectable in the adrenals of CAH rabbits, confirming the previous findings of absent P450scc gene expression by Northern and Western blotting. Cloning and sequencing of a 1336-basepair fragment of rabbit P450scc cDNA (85% of the coding sequence) revealed an approximately 80% identical nucleotide sequence and a 76% identical amino acid sequence compared to the human P450scc cDNA. We conclude that a large deletion mutation in the P450scc gene is most likely responsible for the absent P450scc gene expression resulting in the lethal and feminizing form of CAH in the rabbit. Further investigation of adrenal and gonadal steroidogenic enzyme gene expression in this CAH animal model will provide a greater understanding of the molecular genetics of CAH, while wild-type P450scc gene transfer experiments using CAH adrenals in vitro or in vivo will ultimately characterize the molecular basis of CAH and provide a foundation for CAH gene therapy modality.
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PMID:Inherited congenital adrenal hyperplasia in the rabbit is caused by a deletion in the gene encoding cytochrome P450 cholesterol side-chain cleavage enzyme. 768 38

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.
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PMID:Cloning of factors related to HIV-inducible LBP proteins that regulate steroidogenic factor-1-independent human placental transcription of the cholesterol side-chain cleavage enzyme, P450scc. 1064 52