Disease relevance of Cyp11a1

• 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].
• P450c11 beta mRNA was not detected in the mixed primary glial cultures for the C6 glioma cell line that synthesize P450scc mRNA, suggesting that glial cells do not synthesize P450c11 beta mRNA [2].
• We conclude that, in contrast to P450scc, StAR seems to be evenly expressed in adrenocortical adenomas [3].
• 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 [4].
• Modified expression of steroid 5 alpha-reductase as well as aromatase, but not cholesterol side-chain cleavage enzyme, in the reproductive system of male mice during (Taenia crassiceps) cysticercosis [5].

High impact information on Cyp11a1

• PSF represses transcription of the insulin-like growth factor 1 (IGF1)-inducible gene P450scc by binding to an insulin-like growth factor response element (IGFRE) motif in the gene [6].
• An essential component of regulated steroidogenesis is the translocation of cholesterol from the cytoplasm to the inner mitochondrial membrane where the cholesterol side-chain cleavage enzyme carries out the first committed step in steroidogenesis [7].
• Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold [8].
• Maximal doses of human chorionic gonadotropin, ovine luteinizing hormone, forskolin, or 8-bromoadenosine 3',5'-cyclic monophosphate, stimulated cytochrome P450scc mRNA accumulation 1.5- to 3-fold and progesterone secretion 10- to 100-fold in MA-10 cells [9].
• MA-10 cells are a hormonally homogeneous population, as all cells expressed P450scc mRNA and responded to cAMP equally. cAMP-stimulated accumulation of P450scc mRNA continued in the presence of cycloheximide [9].

Biological context of Cyp11a1

• We observed significant downregulation of Cyp19a1 and upregulation of Star and Cyp11a1 mRNA expression in both COCs and MGCs after in vivo administration of hCG or in vitro treatment with gonadotropins or 8-Br-cAMP [10].
• In addition, targeted mutagenesis of Cyp11a1 also reveals the importance of this gene in steroid secretion, gene regulation, and development of genitalia [11].
• P450scc transcripts are also detectable by in situ hybridization in primitive gut and skin of Fushi tarazu factor 1 null mice, which lack the nuclear receptor steroidogenic factor 1, proving that steroidogenic factor 1 is not required for steroid hydroxylase gene expression at these sites [12].
• In situ hybridization studies reveal novel sites of expression of cholesterol side-chain cleavage cytochrome P450 (P450scc) during murine embryonic development [12].
• The role of SF-1 in P450scc transcription was further confirmed by transactivation of the -186/+12Luc construct employing an SF-1 expression vector after transfection into nonsteroidogenic COS-1 cells [13].

Anatomical context of Cyp11a1

• Male Cyp11a1 null mice are feminized with female external genitalia and underdeveloped male accessory sex organs [14].
• Consistent with this, using transgenic Cyp11a1 reporter mice, we definitively show that steroidogenic cells can migrate from the mesonephros into the XY gonad [15].
• P450scc transcript abundance at these novel sites is a fraction of that in fetal adrenals or testes, suggesting a local rather than an endocrine function [12].
• In doing so, the giant trophoblasts, as any other steroidogenic cell, express high levels of the key steroidogenic enzyme, cholesterol side-chain cleavage cytochrome P450 (P450scc) [16].
• In addition to fetal adrenals and testes, P450scc transcripts localize in situ to the primitive gut and to a subset of unidentified cells in the dermal mesenchyme of embryonic skin [12].

Associations of Cyp11a1 with chemical compounds

• Steroid deficiency syndromes in mice with targeted disruption of Cyp11a1 [14].
• Histological abnormalities of the testes were seen from early developmental stages and were associated with markedly decreased Leydig cell expression of two essential components of testosterone biosynthesis, Cyp11a and the steroidogenic acute regulatory protein [17].
• No changes were observed in the levels of mRNA for P450scc, 3beta-hydroxysteroid dehydrogenase delta4-delta5-isomerase, or P450c21 [18].
• The steroidogenic acute regulatory protein (STAR) participates in steroidogenesis through the mitochondrial transfer of cholesterol to cytochrome P450scc [19].
• In contrast, neither Ca2+ nor Ang II had any effect on the submitochondrial distribution of cytochrome P450scc and 3beta-hydroxysteroid dehydrogenase isomerase [20].

Physical interactions of Cyp11a1

• This inhibition may explain some of the effects observed in AMG treatment which cannot be ascribed to its direct effect on the cytochrome P450scc complex or aromatase [21].
• It is believed that these newly synthesized proteins are instrumental in the delivery of the substrate, cholesterol, to the inner mitochondrial membrane where the cholesterol side-chain cleavage complex converts cholesterol to pregnenolone [22].
• NH2 terminus of PTB-associated splicing factor binds to the porcine P450scc IGF-I response element [23].

Co-localisations of Cyp11a1

• P450scc mRNA colocalized in all sites where StAR mRNA was found, and in bovine liver [24].

Regulatory relationships of Cyp11a1

• Importantly, StAR protein is present in cells that also express P450scc [25].
• Our findings suggest that upon onset of follicular recruitment, CREB-1 mediates FSH/cAMP signaling, which switches to cAMP-independent expression of P450scc in luteinizing granulosa cells expressing Fra-2 [26].
• This is associated with an inhibition of adrenocorticotropic hormone (ACTH) or dibutyryl cAMP-stimulated steroidogenesis and impairment of mitochondrial cholesterol side-chain cleavage activity [27].

Other interactions of Cyp11a1

• Steroidogenic acute regulatory protein expression was lower in pubertal MIS-KO mice compared with WT, whereas 17beta-hydroxy-steroid dehydrogenase and 5alpha-reductase were greater, and P450c17 and P450scc were similar [28].
• In similar studies, chronic treatment with T(3) increased the levels of cytochrome P450scc mRNA by 83%, whereas those of cytochrome P450 17alpha-hydroxylase and 3ss-hydroxysteroid dehydrogenase decreased [29].
• In steroidogenic organs, AKR1B7/MVDP scavenges isocaproaldehyde produced from the cholesterol side-chain cleavage reaction [30].
• Bovine cholesterol side-chain cleavage cytochrome P450 (P450scc; product of the CYP11A gene) gene expression is regulated by gonadotropins via cAMP in the ovary, and by ACTH via cAMP in adrenal cortical cells [31].
• In contrast, although 3 beta HSD mRNA was detected in several of the ovaries examined, the detection of P450scc, P450c17, and P450arom transcripts was rare [32].

Analytical, diagnostic and therapeutic context of Cyp11a1

• To study steroid deficiency in more detail, we used a gene-targeting technique to insert a neo gene into the first exon to disrupt Cyp11a1, the first gene in steroid biosynthetic pathways [14].
• Function of Cyp11a1 in animal models [11].
• ACTH provoked a rapid and sustained increase in P450scc mRNA levels, which decreased very slowly after cessation of treatment without reaching control values 30 h after the last injection [33].
• The 48 kDa antigen was found also in placenta and is probably P450scc, judged by the high correlation of P450scc antibodies with immunodiffusion and immunoblotting results using placental homogenate [4].
• CYP1A1 and steroidogenic enzymes (P450scc, P450c17, 3beta-HSD and 17beta-HSD) mRNA levels were determined by semiquantitative RT-PCR [34].

References