Tissue-Specific, Cyclic Adenosine 3′,5′-Monophosphate-lnduced, and Phorbol Ester-Repressed Transcription from the Human P450c17 Promoter in Mouse Cells

Brentano, Steven T.; Picado-Leonard, James; Mellon, Synthia H.; Moore, Chris C. D.; Miller, Walter L.

doi:10.1210/mend-4-12-1972

Cited by 116 publications

(44 citation statements)

References 31 publications

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“…The cytochrome P450c17a enzyme mediates both steroid 17a-hydroxylase and 17,20 lyase activities and functions at key branch points in human steroid genesis (Brentano et al 1990). In steroidogenesis, cholesterol is first converted to pregnenolone, by an enzyme encoded by CYP11a, and then to progesterone by 3b-hydroxysteroid dehydrogenase; 17a-hydroxylase converts pregnenolone and 17-hydroxyprogesterone, respectively.…”

Section: Introductionmentioning

confidence: 99%

CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients

Chakraborty

Murthy²,

Chintamani

et al. 2007

J Hum Genet

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A single T > C change at the 5¢ promoter region of the CYP17 gene is reported to be associated with increased risk of breast cancer. This study evaluates the influence of genetic polymorphism of CYP17 on breast cancer susceptibility. Two hundred and fortytwo patients with histopathologically confirmed breast cancer and 212 age-matched controls were included in the present study. Information relating to age at onset of the disease, family history and estrogen receptor status was elicited. Investigation for CYP17 polymorphism was carried out in 106 early onset, 80 late onset and 56 familial cases. The frequencies of two CYP17 alleles were also analyzed in 116 (47.9%) cases with known estrogen receptor (ER) status confirmed immunohistochemically. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the polymorphism, and the genotypes identified were assigned as homozygous wild type (A1A1), heterozygous variant (A1A2), and homozygous variant (A2A2). Associations between the various genotypes in patients and controls were investigated with Fisher's exact test. All the tests were two tailed. The results showed that the frequency of heterozygous and homozygous CYP17 genotype was higher in early onset breast cancer patients (94.3%) than in controls (80.3%), and the difference was significant (P = 0.001). A highly statistically significant increased risk in carriers of homozygous A2 allele was found in young patients (P £ 0.001) in comparison with patients having late onset condition (P = 0.260). However, no significant association between the genotype and breast cancer risk was observed among women with strong family history. Further, data had showed that patients (80.6%) with at least one A2 allele tended to exhibit ER-independent cell proliferation, although statistical significance could not be established (P = 0.160). The present findings suggest that CYP17 A2 allele gene polymorphism might play a significant role in breast cancer development in young Indian women.

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Section: Introductionmentioning

confidence: 99%

CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients

Chakraborty

Murthy²,

Chintamani

et al. 2007

J Hum Genet

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“…Hence, the control of adrenal steroidogenic pathways requires a coordinated transcriptional regulation of genes encoding these key enzymes. However, despite numerous studies aimed at understanding the regulation of adrenal steroidogenesis (Waterman & Simpson 1989, Brentano et al 1990, the transcriptional mechanisms are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

The transcriptional regulating protein of 132 kDa (TReP-132) differentially influences steroidogenic pathways in human adrenal NCI-H295 cells

Gizard

Teissier²,

Dufort³

et al. 2004

Journal of Molecular Endocrinology

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Steroid hormones synthesized from cholesterol in the adrenal gland are important regulators of many physiological processes. It is now well documented that the expression of many genes required for steroid biosynthesis is dependent on the coordinated expression of the nuclear receptor steroidogenic factor-1 (SF-1). However, transcriptional mechanisms underlying the species-specific, developmentally programmed and hormone-dependent modulation of the adrenal steroid pathways remain to be elucidated. Recently, we demonstrated that the transcriptional regulating protein of 132 kDa (TReP-132) acts as a coactivator of SF-1 to regulate human P450scc gene transcription in human adrenal NCI-H295 cells. The present study shows that overexpression of TReP-132 increases the level of active steroids produced in NCI-H295 cells. The conversion of pregnenolone to downstream steroids following TReP-132 expression showed increased levels of glucocorticoids, C 19 steroids and estrogens. Correlating with these data, TReP-132 increases P450c17 activities via the induction of transcript levels and promoter activity of the P450c17 gene, an effect that is enhanced in the presence of cAMP or SF-1. In addition, P450aro activity and mRNA levels are highly induced by TReP-132, whereas 3 -hydroxysteroid dehydrogenase type II and P450c11aldo transcript levels are only slightly modulated. Taken together, these results demonstrate that TReP-132 is a trans-acting factor of genes involved in adrenal glucocorticoid, C 19 steroid and estrogen production.

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“…The conversion of pregnenolone and progesterone to their 17␣-hydroxylated products and then to either dehydroepiandrosterone (DHEA) or androstenedione, respectively, is mediated by a single microsomal enzyme, P450c17 (33,34,48), encoded by a single gene (22,39). The pattern of P450c17 expression in steroidogenic tissues is species specific: it is expressed in the human adrenal and gonad but not placenta (9,11,15,44), and it is expressed in the rodent gonad and placenta but not adrenal (19,23,25).…”

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Deletion of the Mouse P450c17 Gene Causes Early Embryonic Lethality

Bair

Mellon

2004

Molecular and Cellular Biology

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Dehydroepiandrosterone (DHEA), a 19-carbon precursor of sex steroids, is abundantly produced in the human but not the mouse adrenal. However, mice produce DHEA and DHEA-sulfate (DHEAS) in the fetal brain. DHEA stimulates axonal growth from specific populations of mouse neocortical neurons in vitro, while DHEAS stimulates dendritic growth from those cells. The synthesis of DHEA and sex steroids, but not mouse glucocorticoids and mineralocorticoids, requires P450c17, which catalyzes both 17␣-hydroxylase and 17,20-lyase activities. We hypothesized that P450c17-knockout mice would have disordered sex steroid synthesis and disordered brain DHEA production and thus provide phenotypic clues about the functions of DHEA in mouse brain development. We deleted the mouse P450c17 gene in 127/SvJ mice and obtained several lines of mice from two lines of targeted embryonic stem cells. Heterozygotes were phenotypically and reproductively normal, but in all mouse lines, P450c17 ؊/؊ zygotes died by embryonic day 7, prior to gastrulation. The cause of this early lethality is unknown, as there is no known function of fetal steroids at embryonic day 7. Immunocytochemistry identified P450c17 in embryonic endoderm in E7 wild-type and heterozygous embryos, but its function in these cells is unknown. Enzyme assays of wild-type embryos showed a rapid rise in 17-hydroxylase activity between E6 and E7 and the presence of C 17,20 -lyase activity at E7. Treatment of pregnant females with subcutaneous pellets releasing DHEA or 17-OH pregnenolone at a constant rate failed to rescue P450c17 ؊/؊ fetuses. Treatment of normal pregnant females with pellets releasing pregnenolone or progesterone did not cause fetal demise. These data suggest that steroid products of P450c17 have heretofore-unknown essential functions in early embryonic mouse development.

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Tissue-Specific, Cyclic Adenosine 3′,5′-Monophosphate-lnduced, and Phorbol Ester-Repressed Transcription from the Human P450c17 Promoter in Mouse Cells

Cited by 116 publications

References 31 publications

CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients

CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients

The transcriptional regulating protein of 132 kDa (TReP-132) differentially influences steroidogenic pathways in human adrenal NCI-H295 cells

Deletion of the Mouse P450c17 Gene Causes Early Embryonic Lethality

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