Effects of transforming growth factor-β on human fetal adrenal steroid production

Ak, Stankovic; Ld, Dion; Cr, Parker

doi:10.1016/0303-7207(94)90002-7

Cited by 51 publications

(20 citation statements)

References 21 publications

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“…Following isolation, cells were either frozen or subcultured onto 60-mm culture dishes for subsequent steroid assay or real time RT-PCR. Fetal adrenal cells were isolated essentially as described (20) and cultured in Dulbecco's modified Eagle's medium/F-12 medium, 1% ITS (BD Biosciences, Bedford, MA), 10% cosmic calf serum, and antibiotics.…”

Section: Methodsmentioning

confidence: 99%

The Orphan Nuclear Receptor NGFIB Regulates Transcription of 3β-Hydroxysteroid Dehydrogenase

Bassett

Suzuki

Sasano

et al. 2004

Journal of Biological Chemistry

118

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3␤-Hydroxysteroid dehydrogenase type 2 (HSD3B2) is a steroid-metabolizing enzyme that is essential for adrenal production of mineralocorticoids and glucocorticoids. Thus, HSD3B2 is expressed at high levels in the glomerulosa and fasciculata, where these steroids are produced. In contrast, the production of dehydroepiandrosterone (DHEA) and DHEA sulfate in the adrenal reticularis is inversely correlated with the expression of HSD3B2. The reasons for the zonal expression of HSD3B2 are not known but represent an important aspect in the biochemical zonation of the adrenal. Using microarray, real time reverse transcriptase-PCR, immunohistochemistry, and HSD3B2 promoter analysis, we demonstrate that the NGFIB family of nuclear hormone receptors plays a critical part in the regulation of HSD3B2 transcription and may play an important role in the functional zonation of the adrenal gland. Microarray analysis of cortisol-versus DHEA sulfate-producing adrenal tissue demonstrated that NGIFB paralleled expression of HSD3B2 with expression much higher in cortisol-producing adrenal tissue; this observation was also demonstrated using real time reverse transcriptase-PCR analysis. In addition, immunohistochemistry confirmed that within adult and fetal adrenal gland NGFIB expression paralleled expression of HSD3B2. Transient transfections into H295R adrenal cells demonstrated that NGFIB family members enhanced HSD3B2 reporter activity but had no effect on a 17␣-hydroxylase (CYP17) promoter construct. Deletion and mutational analyses of the 5-flanking region of the HSD3B2 gene identified a consensus NGFIB response element that bound NGFIB in mobility shift assays. Infection of cultured human adrenal cells with adenovirus-containing NGFIB increased cortisol production by 8-fold and increased expression of HSD3B2 mRNA 26-fold over that observed in mock-infected cells. In primary cultures of adrenal cells, ACTH, an activator of HSD3B2, rapidly induced expression of NGFIB. These results suggest that NGFIB plays a crucial role in adrenal zonation by regulating HSD3B2 gene transcription.The enzyme 3␤-hydroxysteroid dehydrogenase type 2 (HSD3B2) 1 is essential for the adrenal biosynthesis of mineralocorticoids (aldosterone) and glucocorticoids (cortisol), but its expression is inversely associated with that of the adrenal androgens (DHEA) (1). HSD3B2 catalyzes the oxidation and isomerization of 3␤-hydroxy-5-ene (⌬ 5 ) steroids into 3-keto-4-ene (⌬ 4 ) steroids, thereby permitting the adrenal gland to synthesize progesterone and 17␣-hydroxyprogesterone from their pregnenolone and 17␣-hydroxypregnenolone precursors (2). HSD3B2 can compete with CYP17 for the metabolism of pregnenolone and 17␣-hydroxypregnenolone and thus influence the production of aldosterone versus cortisol or DHEA (3). High HSD3B2 expression combined with low CYP17 activity will favor aldosterone synthesis and oppose cortisol and adrenal androgen synthesis. Conversely, low HSD3B2 expression coupled with high CYP17 activity will favor adrenal androgen production.The human...

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Section: Methodsmentioning

confidence: 99%

The Orphan Nuclear Receptor NGFIB Regulates Transcription of 3β-Hydroxysteroid Dehydrogenase

Bassett

Suzuki

Sasano

et al. 2004

Journal of Biological Chemistry

118

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“…Induction of melatonin release represents a positive feedback loop, because melatonin itself enhances IFN-␥ production (461). TGF-␤ exerts an inhibitory effect on steroidogenesis (462) and seems to be involved in fetal (463,464) and adult (465) steroidogenesis, where it seems to reduce the synthesis of dehydroepiandrosterone sulfate.…”

Section: Ectopic Expression Of Cytokines As Therapeutic Genesmentioning

confidence: 99%

Endocrine Aspects of Cancer Gene Therapy

2004

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The field of cancer gene therapy is in continuous expansion, and technology is quickly moving ahead as far as gene targeting and regulation of gene expression are concerned. This review focuses on the endocrine aspects of gene therapy, including the possibility to exploit hormone and hormone receptor functions for regulating therapeutic gene expression, the use of endocrine-specific genes as new therapeutic tools, the effects of viral vector delivery and transgene expression on the endocrine system, and the endocrine response to viral vector delivery. Present ethical concerns of gene therapy and the risk of germ cell transduction are also discussed, along with potential lines of innovation to improve cell and gene targeting.

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“…TGFβ1 is known to influence steroid biosynthesis in adrenocortical cells by decreasing 3β-HSD expression [16–18]. In breast cancer cells, it enhances the action of reductive 17β-HSD activity [19,20].…”

Section: Introductionmentioning

confidence: 99%

TGFβ1 alters androgenic metabolites and hydroxysteroid dehydrogenase enzyme expression in human prostate reactive stromal primary cells: Is steroid metabolism altered by prostate reactive stromal microenvironment?

Piao

Wiesenfeld

Sprando

et al. 2013

The Journal of Steroid Biochemistry and Molecular Biology

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The inflammatory tissue microenvironment can be an active promoter in preneoplastic cancer lesions. Altered steroid hormone metabolism as induced by the inflammatory microenvironment may contribute to epithelial cancer progression. Dehydroepiandrosterone sulfate (DHEAS) is the most abundant endogenous steroid hormone present in human serum and can be metabolized to DHEA, androgens and/or estrogens in peripheral tissues. We have previously reported that TGFβ1-induced reactive prostate stromal cells increase DHEA metabolism to active androgens and alter prostate cancer cell gene expression. While much of the focus on mechanisms of prostate cancer and steroid metabolism is in the epithelial cancer cells, this study focuses on TGFβ1-induced effects on DHEA metabolic pathways and enzymes in human prostate stromal cells. In DHEA-treated primary prostate stromal cells, TGFβ1 produced time- and dose-dependent increases in metabolism of DHEA to androstenedione and testosterone. Also TGFβ1-treated prostate stromal cells exhibited changes in the gene expression of enzymes involved in steroid metabolism including up-regulation of 3β hydroxysteroid dehydrogenase (HSD), and down-regulation of 17βHSD5, and 17βHSD2. These studies suggest that reactive prostate stroma and the inflammatory microenvironment may contribute to altered steroid metabolism and increased intratumoral androgens.

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Effects of transforming growth factor-β on human fetal adrenal steroid production

Cited by 51 publications

References 21 publications

The Orphan Nuclear Receptor NGFIB Regulates Transcription of 3β-Hydroxysteroid Dehydrogenase

The Orphan Nuclear Receptor NGFIB Regulates Transcription of 3β-Hydroxysteroid Dehydrogenase

Endocrine Aspects of Cancer Gene Therapy

TGFβ1 alters androgenic metabolites and hydroxysteroid dehydrogenase enzyme expression in human prostate reactive stromal primary cells: Is steroid metabolism altered by prostate reactive stromal microenvironment?

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