Disease relevance of Cyp17a1

• This results from higher levels of steroidogenic activity per fetal Leydig cell, as indicated by the hypertrophy of these cells and the higher levels of mRNA for StAR, P450c17 and P450scc in the testis, for a similar number of Leydig cells [1].
• Steroidogenic enzymes P450scc, P450c17 and P450c21 have recently been shown to be the main autoantigens recognized by sera from patients with autoimmune polyglandular syndrome (APS type I) with or without Addison's disease [2].

High impact information on Cyp17a1

• There was also a slight decrease in 17-OH-progesterone compared to the more significant decrease in testosterone, suggesting that MIS might be regulating the lyase activity of cytochrome P450c17 hydroxylase/lyase (Cyp17), but not its hydroxylase activity [3].
• These data suggest that steroid products of P450c17 have heretofore-unknown essential functions in early embryonic mouse development [4].
• The synthesis of DHEA and sex steroids, but not mouse glucocorticoids and mineralocorticoids, requires P450c17, which catalyzes both 17 alpha-hydroxylase and 17,20-lyase activities [4].
• Immunocytochemistry identified P450c17 in embryonic endoderm in E7 wild-type and heterozygous embryos, but its function in these cells is unknown [4].
• Heterozygotes were phenotypically and reproductively normal, but in all mouse lines, P450c17(-/-) zygotes died by embryonic day 7, prior to gastrulation [4].

Biological context of Cyp17a1

• Protein kinase A (PKA) inhibition with H-89 blocked Cyp17 mRNA induction, suggesting that MIS interferes with the PKA signal transduction pathway [5].
• During embryonic development, however, we discovered transient expression of P450c17 in a subset of adrenocortical cells in the fetal mouse adrenal [6].
• In addition, phosphorylation of the cAMP responsive element binding protein (CREB) was not detected following 50 micro M cAMP exposure, a concentration sufficient for Cyp17 mRNA induction [5].
• To identify regions necessary for cAMP-induced transcription, 5'-flanking regions of Cyp17 were fused with the chloramphenicol acetyltransferase (CAT) reporter gene and transiently transfected into MA-10 tumor Leydig cells [7].
• In contrast, no repression by dihydrotestosterone was observed when the -1021 bp Cyp17-CAT construct was cotransfected with a human AR expression plasmid missing the second zinc finger of the DNA-binding domain, indicating that DNA binding is involved in AR-mediated repression of Cyp17 expression [8].

Anatomical context of Cyp17a1

• Treatment of Leydig cells with 8-Br-cAMP caused a 150.7 +/- 32.9-fold increase in testosterone production and marked stimulation of P450scc and P450c17 mRNA and protein accumulation [9].
• Adrenal glands from adult mice contain mRNAs encoding steroid hydroxylases required to produce corticosterone and aldosterone but not cortisol (little P450c17 mRNA) [6].
• We deleted the mouse P450c17 gene in 127/SvJ mice and obtained several lines of mice from two lines of targeted embryonic stem cells [4].
• Treatment of pregnant females with subcutaneous pellets releasing DHEA or 17-OH pregnenolone at a constant rate failed to rescue P450c17(-/-) fetuses [4].
• The transcriptional strategy for the expression of P450c17 is clearly different in the brain from that in the adrenal or gonad [10].

Associations of Cyp17a1 with chemical compounds

• The inhibition of testosterone production is parallel to the inhibition of P450c17 messenger RNA and protein levels [11].
• These data suggest that the absence of fetal ovarian steroid hormone production is the result of lack of expression of at least three of the steroidogenic enzymes, P450scc, P450c17, and P450arom [12].
• On the other hand, both proopiomelanocortin-derived peptide beta-endorphin and corticosterone concentration levels are elevated in Wnt-deficient mice, and the expression of Cyp17 is altered in Wnt-4 mutant females, so that it mimics the pattern specific for males [13].
• The methodology was verified by confirming the presence of previously characterized TP-regulated genes, including Pem in Sertoli cells and Cyp17a1 in Leydig cells [14].
• Northern analysis showed that, in both MIS-treated rats and mice, the mRNA for Cyp17, which catalyzes the committed step in androgen synthesis, was down-regulated [3].

Physical interactions of Cyp17a1

• Consensus sequence of transcription factor SF-1 binding site and putative binding site in the 5' flanking regions of genes encoding mouse steroidogenic enzymes 3betaHSDI and Cyp17 [15].

Regulatory relationships of Cyp17a1

• The inhibitory effect of TNF alpha on 8-Br-cAMP-induced P450c17 mRNA expression was reversible [9].
• Müllerian-inhibiting substance (MIS) reduces testosterone synthesis in Leydig cells by inhibiting cytochrome P450C17 hydroxylase/C17-20 lyase expression [16].
• IL-1 beta completely inhibited cAMP-stimulated testosterone production and P450c17 mRNA expression [17].

Other interactions of Cyp17a1

• PMA, a known activator of PKC, and TNF alpha had a similar inhibitory effect on P450c17 expression, testosterone production, and Cyp17-CAT activity.(ABSTRACT TRUNCATED AT 400 WORDS)[11]
• Testosterone biosynthesis in Leydig cells is dependent on the action of 17 alpha-hydroxylase/C17-20 lyase cytochrome P450 (P450c17), which is encoded by the Cyp17 gene [11].
• In contrast, Cyp17 and Cyp19 expression were elevated in alphaERKO but normal in betaERKO and alphabetaERKO [18].
• The expression of steroidogenic acute regulatory protein and 17beta-hydroxysteroid dehydrogenase was lower in adult MIS-KO mice, whereas that of 5alpha-reductase, P450c17, and P450scc was similar [19].
• An additional cross, (BALB/c x CAST/Ei) F(1) x BALB/c, was used to map markers around this mutation as well as to map the potential candidate genes, Fgf8 and Cyp17 [20].

Analytical, diagnostic and therapeutic context of Cyp17a1

• Treatment of normal mouse Leydig cells in primary culture with 50 microM 8-bromo-cAMP (cAMP) plus 1 ng/ml TNF alpha or 10 nM PMA caused a similar (approximately 90%) decrease in testosterone accumulation and cAMP-stimulated P450c17 messenger RNA levels compared to those after treatment with cAMP alone [11].
• Immunocytochemistry and in situ hybridization in the mouse fetus show that the ontogeny and distribution of SET in the developing nervous system are consistent with SET being crucial for initiating P450c17 transcription [10].
• CYP1A1 and steroidogenic enzymes (P450scc, P450c17, 3beta-HSD and 17beta-HSD) mRNA levels were determined by semiquantitative RT-PCR [21].
• Northern blot analysis indicated that accumulation of messenger RNA for P450c17 was not significantly altered [22].

References