| cytochrome P450 family 17 subfamily A member 1 | OKDB#: 20 |
| Symbols: | CYP17A1 | Species: | human | ||
| Synonyms: | CPT7, CYP17, S17AH, P450C17 | Locus: | 10q24.32 in Homo sapiens |
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| General Comment |
P450C17 is a single enzyme that mediates both 17-alpha-hydroxylase and 17,20-lyase activity; It catalyzes both 17-alpha-hydroxylation of pregnenolone and progesterone and 17,20-lysis of 17-alpha-hydroxypregnenolone and 17-alpha-hydroxyprogesterone. Both hydroxylation and C17,20 lyase activity occur at the same catalytic site (Chung et al., 1987). Postmenopausal ovaries studied expressed the
P450c17 gene at the messenger RNA level (Jose et al., 1999). In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism (Nestler and Jakubowicy, 1996).
Gene expression increased. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression. Agca C et al. The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and structural changes that ultimately lead to ovulation and the formation of corpora lutea. The objective of the study was to examine gene expression in ovarian follicles (n = 11) collected from pigs (Sus scrofa domestica) approaching estrus (estrogenic preovulatory follicle; n = 6 follicles from two sows) and in ovarian follicles collected from pigs on the second day of estrus (preovulatory follicles that were luteinized but had not ovulated; n = 5 follicles from two sows). The follicular status within each follicle was confirmed by follicular fluid analyses of estradiol and progesterone ratios. Microarrays were made from expressed sequence tags that were isolated from cDNA libraries of porcine ovary. Gene expression was measured by hybridization of fluorescently labeled cDNA (preovulatory estrogenic or -luteinized) to the microarray. Microarray analyses detected 107 and 43 genes whose expression was decreased or increased (respectively) during the transition from preovulatory estrogenic to -luteinized (P<0.01). Cells within preovulatory estrogenic follicles had a gene-expression profile of proliferative and metabolically active cells that were responding to oxidative stress. Cells within preovulatory luteinized follicles had a gene-expression profile of nonproliferative and migratory cells with angiogenic properties. Approximately, 40% of the discovered genes had unknown function.///////thecal cell marker
NCBI Summary: This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum. It has both 17alpha-hydroxylase and 17,20-lyase activities and is a key enzyme in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens. Mutations in this gene are associated with isolated steroid-17 alpha-hydroxylase deficiency, 17-alpha-hydroxylase/17,20-lyase deficiency, pseudohermaphroditism, and adrenal hyperplasia. [provided by RefSeq, Jul 2008] |
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| General function | Enzyme, Oxidoreductase, Lyase | ||||
| Comment | Increased protein expression of LHCG receptor and 17a-hydroxylase/17-20-lyase in human polycystic ovaries. Comim FV 2013 et al. STUDY QUESTION Does the expression of LHCG receptor (LHCGR) protein and key enzymes in the androgen biosynthetic pathway differ in normal human versus polycystic ovarian tissue? SUMMARY ANSWER LHCGR and 17a-hydroxylase/17-20-lyase (CYP17A1) protein levels are increased in polycystic ovaries (PCOs). WHAT IS KNOWN ALREADY The predominant source of excess androgen secretion in women with polycystic ovary syndrome (PCOS) is ovarian theca cells but few studies have directly assessed the presence and abundance of protein for key molecules involved in androgen production by theca, including LHCGR and the rate-limiting enzyme in androgen production, CYP17A1. STUDY DESIGN, SIZE, DURATION This is a laboratory-based, cross-sectional study comparing protein expression of key molecules in the androgen biosynthetic pathway in archived ovarian tissue from women with normal ovaries (n = 10) with those with PCOs (n = 16). PARTICIPANTS/MATERIALS, SETTING, METHODS A quantitative morphometric study was performed using sections of archived human ovaries (n = 26) previously characterized as normal or polycystic. The distribution and abundance of LHCGR, CYP17A1, 3?hydroxysteroid dehydrogenase type 2 (3?SDII) and 17?hydroxysteroid dehydrogenase type 5 (17?SD5) proteins were evaluated by immunohistochemistry and quantified. MAIN RESULTS AND THE ROLE OF CHANCE A higher proportion of theca cells from anovulatory PCO expressed LHCGR protein when compared with control ovaries (P = 0.01). A significant increase in the intensity of immunostaining for CYP17A1 was identified in antral follicles in sections of PCO compared with ovaries from normal women (P = 0.04). LIMITATIONS, REASONS FOR CAUTION As the study used formalin-fixed ovarian tissue sections, it was not possible to carry out studies 'in vitro' using the same ovarian tissues in order to also demonstrate increased functional activity of LHCGR and CYP17A1. WIDER IMPLICATIONS OF THE FINDINGS The data are in keeping with the results of previous studies in isolated theca cells and support the notion of an intrinsic abnormality of theca cell androgen production in women with PCOS. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by a Programme Grant, G0802782, from the Medical Research Council (MRC) UK. F.V.C. was supported by Capes Foundation (Brazilian Ministry of Education). The authors have no conflicts of interest to disclose. ///////////////////////// Phosphorylation of Human P450c17 by p38a Selectively Increases 17,20 Lyase Activity and Androgen Biosynthesis. Tee MK 2013 et al. Cytochrome P450c17, a steroidogenic enzyme encoded by the CYP17A1 gene, catalyzes the steroid 17a-hydroxylation needed for glucocorticoid synthesis, which may or may not be followed by 17,20 lyase activity, needed for sex steroid synthesis. Whether or not P450c17 catalyzes 17,20 lyase activity is determined by three post-translational mechanisms influencing availability of reducing equivalents donated by P450 oxidoreductase (POR). These are increased amounts of POR, the allosteric action of cytochrome b5 to promote POR-P450c17 interaction, and Ser/Thr phosphorylation of P450c17, which also appears to promote POR-P450c17 interaction. The kinase(s) that phosphorylate P450c17 are unknown. In a series of kinase inhibition experiments, the pyridinyl imidazole drugs SB202190 and SB203580 inhibited 17,20 lyase but not 17a-hydroxylase activity in human adrenocortical NCI-H295A cells, suggesting an action on p38a or p38? Co-transfection of non-steroidogenic COS1 cells with P450c17 and p38 expression vectors showed that p38a, but not p38? conferred 17,20 lyase activity on P450c17. Antiserum to P450c17 co-immunoprecipitated P450c17 and both p38 isoforms, however knockdown of p38a, and not p38? inhibited 17,20 lyase activity in NCI-H295A cells. Bacterially expressed human P450c17 was phosphorylated by p38a in vitro at a non-cannonical site, conferring increased 17,20 lyase activity. This phosphorylation increased the maximum velocity, but not the Michaelis constant, of the 17,20 lyase reaction. p38a phosphorylates P450c17 in a fashion that confers increased 17,20 lyase activity, implying that the production of adrenal androgens (adrenarche) is a regulated event. ///////////////////////// The bovine genome contains three differentially methylated paralogous copies of the P450c17 encoding gene (CYP17A1). Vanselow J et al. CYP17A1 encodes the key enzyme of androgen biosynthesis, P450c17. The gene is expressed in a number of steroidogenic tissues among them testis, ovary, placenta and adrenal gland. The proper analysis of CYP17A1 expression and of epigenetic parameters however, is hampered by the presence of more than one copy of the gene within the bovine genome. Therefore, as a prerequisite for future studies we characterized these copies and analyzed their promoter methylation and expression profiles in different tissues. DNA methylation levels were determined by bisulfite modification, amplification, cloning and sequencing. Transcription was analyzed by RT-PCR. From bovine genomic DNA three different CYP17A1 promoter sequences could be amplified with a sequence similarity of 94.8, 95.6 and 98.7%. Based on these sequences we could reconstruct by in silico analysis the promoter regions and eight potentially coding exons of two loci, CYP17A1a and CYP17A1b, and the promoter region and truncated first exon of a third locus, CYP17A1x. By using locus-specific primers, only transcripts of CYP17A1a, but not of CYP17A1b could be detected in testis, epididymis, theca, corpus luteum, placental cotyledons, adrenal gland and preoptic brain area. Methylation analysis revealed that only the CYP17A1a promoter was hypo-methylated in the tested P450c17 active tissues, whereas both other copies showed higher levels of methylation. From these data we conclude that the bovine genome contains three paralogous copies of the CYP17A1 gene, of which two (CYP17A1b and CYP17A1x) might be silenced by epigenetic modification (promoter methylation). Steroid profiles in ovarian follicular fluid in women with and without polycystic ovary syndrome, analyzed by liquid chromatography-tandem mass spectrometry. Naessen T et al. OBJECTIVE: To compare steroid concentrations and steroid product-to-precursor ratios in ovarian follicular fluid (FF) from women with polycystic ovary syndrome (PCOS) and from regularly menstruating women in their early follicular phase, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Polycystic ovary syndrome involves abnormal regulation of the steroidogenic enzymes, leading to arrest of follicle development. DESIGN: Case-control study. SETTING: University hospital clinic. PATIENT(S): Follicular fluid from size-matched ovarian follicles (5-8 mm) in 27 nonstimulated women with PCOS and in 21 women without PCOS was sampled. Thirteen steroids were quantitated from 40 muL of FF, using LC-MS/MS. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of steroids in the FF and product-to-precursor ratios (enzyme activity) were compared between the groups. RESULT(S): In women with PCOS, ovarian FF contained higher concentrations of individual and total androgens, lower individual and total estrogens (E), and a lower total E-to-androgen ratio, compared with regularly menstruating women. The product-to-precursor concentration ratios indicated higher CYP17-linked and lower CYP19-linked (aromatase) enzyme activity. Receiver operating characteristic plots indicated the early CYP17 step (17-OH5P/5P) being highly important for the prevalence of PCOS (c = 0.95). CONCLUSION(S): The women with PCOS had higher ovarian CYP17-linked and lower CYP19-linked (aromatase) enzyme activity, confirming previous data. Multiple steroid assessments from minute volumes including FF from nonstimulated ovaries, using LC-MS/MS, might be useful in research, clinical endocrinology, and in IVF. | ||||
| Cellular localization | Other Membrane | ||||
| Comment | family123/////////P450C17 is bound to the smooth endoplasmic reticulum. | ||||
| Ovarian function | Steroid metabolism, Luteinization, Oocyte maturation | ||||
| Comment | Androgens promote maturation and signaling in mouse oocytes independent of transcription: a release of inhibition model for mammalian oocyte meiosis. Gill A,et al . Normal fertility in females depends upon precise regulation of oocyte meiosis. Oocytes are arrested in prophase I of meiosis until just before ovulation, when meiosis, or maturation, is triggered to resume. Whereas sex steroids appear to promote maturation in fish and amphibians, the factors regulating mammalian oocyte maturation have remained obscure. We show here that, similar to lower vertebrates, steroids may play a role in promoting the release of meiotic inhibition in mammals. Specifically, testosterone induced maturation of mouse oocytes arrested in meiosis, as well as activation of MAPK and cyclin-dependent kinase 1 signaling. These responses appeared to be transcription independent and might involve signaling through classical androgen receptors expressed in the oocytes. Our results are the first to show that sex steroids can modulate meiosis in mammalian oocytes and suggest a model whereby dominant ovarian follicles in mammals may produce sufficient androgen and/or other steroids to overcome constitutive inhibitory signals and allow oocyte maturation and subsequent ovulation to occur. Effect of small interfering RNAs of cytochrome P450 17alpha-hydroxylase/17,20-lyase (CYP17) on androgen biosynthesis in theca cells. Du J et al. Polycystic ovary syndrome (PCOS) is associated with a variety of endocrinologic and metabolic abnormalities, with clinical features of hyperandrogenism and hyperandrogenemia. Cytochrome P450 17alpha-hydroxylase/17,20-lyase (CYP17) is critical in androgen biosynthesis, and CYP17 mRNA expression was proven augmented in PCOS theca cells. To demonstrate whether RNA interference (RNAi) could lower the androgen concentration in theca cells, small interfering RNA (siRNA) targeting the CYP17 gene was co-cultured with exogenous CYP17 in HeLa cells and endogenous CYP17 of theca cells. CYP17 gene expression was measured by fluorescent microscopy, flow cytometry and real-time reverse transcription-polymerase chain reaction analysis. Androstenedione and progesterone concentrations were measured by ELISA. RNAi effectively reduced the expression of exogenous CYP17 in HeLa cells by up to 50%. The CYP17 mRNA and androstenedione production of theca cells were slightly, but not significantly, reduced when compared with non-specific siRNA. | ||||
| Expression regulated by | LH, Steroids, Growth Factors/ cytokines, Eicosanoids | ||||
| Comment | Gene expression decreased. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression. Agca C et al. The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and structural changes that ultimately lead to ovulation and the formation of corpora lutea. The objective of the study was to examine gene expression in ovarian follicles (n = 11) collected from pigs (Sus scrofa domestica) approaching estrus (estrogenic preovulatory follicle; n = 6 follicles from two sows) and in ovarian follicles collected from pigs on the second day of estrus (preovulatory follicles that were luteinized but had not ovulated; n = 5 follicles from two sows). The follicular status within each follicle was confirmed by follicular fluid analyses of estradiol and progesterone ratios. Microarrays were made from expressed sequence tags that were isolated from cDNA libraries of porcine ovary. Gene expression was measured by hybridization of fluorescently labeled cDNA (preovulatory estrogenic or -luteinized) to the microarray. Microarray analyses detected 107 and 43 genes whose expression was decreased or increased (respectively) during the transition from preovulatory estrogenic to -luteinized (P<0.01). Cells within preovulatory estrogenic follicles had a gene-expression profile of proliferative and metabolically active cells that were responding to oxidative stress. Cells within preovulatory luteinized follicles had a gene-expression profile of nonproliferative and migratory cells with angiogenic properties. Approximately, 40% of the discovered genes had unknown function. | ||||
| Ovarian localization | Theca, Luteal cells, Stromal cells | ||||
| Comment | Molecular Mechanism for Repression of 17{alpha}-Hydroxylase Expression and Androstenedione Production in Granulosa Cells. Patel SS et al. Context: According to the traditional two-cell two-gonadotropin model of follicular steroidogenesis, androgen production arises exclusively from theca cells. The granulosa cells, in turn, utilize androstenedione and testosterone, which are aromatized into estrone and estradiol, respectively. Differential expression of the activator protein-1 (AP-1) transcription factor, c-fos, has been postulated to result in distinct patterns of steroidogenesis in the theca and granulosa cell compartments. We hypothesize that c-fos functions to inhibit the production of 17alpha-hydroxylase 17,20 lyase (CYP17) in granulosa cells, thereby suppressing androgen synthesis. Objective: Our objective was to define the role of c-fos in the regulation of CYP17 production in granulosa cells. Design and Methods: Human luteinized granulosa (HGL5) cells were utilized for all experiments. The following techniques were used: mRNA extraction, steroid quantification, small interfering RNA silencing, microarray analysis, and immunohistochemistry. Results: Immunohistochemistry studies demonstrated significant staining of c-fos in the granulosa cell layer, but absent staining for CYP17. Conversely, the theca cell layer did not stain for c-fos, but staining was evident for CYP17. Treatment of HGL5 cells with the MAPK kinase inhibitor PD98059 resulted in an 11-fold increase in CYP17 mRNA levels. In c-fos gene silenced cells, CYP17 mRNA levels increased 8-fold. Androstenedione production was increased 13-fold after treatment with PD98059. Conclusions: These results suggest that the AP-1 transcription factor, c-fos, may be one of the factors responsible for CYP17 repression and hence suppression of androstenedione production in granulosa cells. This may provide an explanation for the lack of CYP17 in granulosa cells. This enzyme is found in theca-luteal cells at early stage of luteinization. Thecal cell cytochrome P450(17)alpha and the regulation of its content and mRNA by LH are pivotal to the biosynthesis of androgens, the obligatory precursors for estradiol biosynthesis and the consequent development of preovulatory follicles (Hedin et al., 1987). | ||||
| Follicle stages | Secondary, Antral, Preovulatory, Corpus luteum | ||||
| Comment | Molecular Mechanism for Repression of 17{alpha}-Hydroxylase Expression and Androstenedione Production in Granulosa Cells. Patel SS et al. Context: According to the traditional two-cell two-gonadotropin model of follicular steroidogenesis, androgen production arises exclusively from theca cells. The granulosa cells, in turn, utilize androstenedione and testosterone, which are aromatized into estrone and estradiol, respectively. Differential expression of the activator protein-1 (AP-1) transcription factor, c-fos, has been postulated to result in distinct patterns of steroidogenesis in the theca and granulosa cell compartments. We hypothesize that c-fos functions to inhibit the production of 17alpha-hydroxylase 17,20 lyase (CYP17) in granulosa cells, thereby suppressing androgen synthesis. Objective: Our objective was to define the role of c-fos in the regulation of CYP17 production in granulosa cells. Design and Methods: Human luteinized granulosa (HGL5) cells were utilized for all experiments. The following techniques were used: mRNA extraction, steroid quantification, small interfering RNA silencing, microarray analysis, and immunohistochemistry. Results: Immunohistochemistry studies demonstrated significant staining of c-fos in the granulosa cell layer, but absent staining for CYP17. Conversely, the theca cell layer did not stain for c-fos, but staining was evident for CYP17. Treatment of HGL5 cells with the MAPK kinase inhibitor PD98059 resulted in an 11-fold increase in CYP17 mRNA levels. In c-fos gene silenced cells, CYP17 mRNA levels increased 8-fold. Androstenedione production was increased 13-fold after treatment with PD98059. Conclusions: These results suggest that the AP-1 transcription factor, c-fos, may be one of the factors responsible for CYP17 repression and hence suppression of androstenedione production in granulosa cells. This may provide an explanation for the lack of CYP17 in granulosa cells. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
4 mutations
Species: human
Species: human
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | March 12, 1999, midnight | by: |
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| last update: | Oct. 19, 2020, 1:35 p.m. | by: | hsueh email: |
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