Human steroidogenic acute regulatory protein: functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13.

Sugawara, Teruo; Holt, John A.; Driscoll, Deborah A.; Strauss, Jerome F.; Lin, Dong; Miller, Walter L.; Patterson, David; Clancy, Kevin; Hart, Iris; Clark, Barbara J.

doi:10.1073/pnas.92.11.4778

Cited by 354 publications

(182 citation statements)

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“…Primary points of control in steroidogenesis are the transport of cholesterol from intracellular stores to the inner mitochondrial membrane, and the subsequent conversion of cholesterol to pregnenolone by the cholesterol side-chain cleavage enzyme (P450scc) [6], which initiates the synthesis of all steroid hormones. The StAR protein mediates the rate-limiting and acutely regulated step in steroidogenesis [15,29,30]. LH stimulation is mediated by the LH receptor at the first step of the signaling pathway, and subsequently intercellular cAMP increases to stimulate the transcription of the StAR in mouse MA-10 cells [36].…”

Section: Discussionmentioning

confidence: 99%

Progression of the Dose-Related Effects of Estrogenic Endocrine Disruptors, an Important Factor in Declining Fertility, Differs between the Hypothalamo-Pituitary Axis and Reproductive Organs of Male Mice

Warita

Sugawara

Yue

et al. 2006

The Journal of Veterinary Medical Science

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ABSTRACT. For the purpose of investigation of working mechanisms in endocrine disruptors, we evaluated the dose-related effects of fetal and/or neonatal exposure to an estrogenic compound on the male reproductive organs in adult mice, particularly with respect to gene expression of steroidogenic acute regulatory protein (StAR). The pregnant ICR mice were given subcutaneous injections of 10 µg/day/ animal of diethylstilbestrol (DES) to subject the fetal mice to in utero exposure (IUE). Subsequently, the newborn male mice were subjected to neonatal exposure (NE) by treatment with vehicle or 0.1-10 µg/day/animal of DES. Fertility rates of each group were as follows: control, 100%; IUE only, 60%; IUE+NE 0.1 µg, 25%; IUE+NE 1 µg, 0%; IUE+NE 10 µg, 0%. In general histology, germ cell layers in the seminiferous tubules were thinned in the group of IUE+NE 10 µg. Hypoplasia of the Leydig cells, in which the staining intensity of eosin was diminished, was also observed in the groups of IUE+NE 0.1-10 µg. The androgen receptor (AR) and estrogen receptor alpha (ERα) immunoexpression in the Leydig cells of IUE+NE 1-10 µg was slightly lower than that in the controls. Longterm dysfunction of the hypothalamo-pituitary-testicular axis, including sustained hypoproduction of gonadotropin and testosterone, and altered expressions of steroid hormone receptors and StAR genes were observed. The hypothalamo-pituitary control of gonadotropin secretion may be affected by the smaller doses of estrogenic agents than the reproductive organs. Furthermore, the fertility rate in the male mice exposed to this estrogenic agent was closely correlated with the testosterone levels, and even more so with the rate-limiting factor of steroidogenesis, StAR. This finding suggests that endocrine disruptors have an important pronounced effect on StAR gene expression. KEY WORDS: diethylstilbestrol (DES), endocrine disruptors, fertility rate, fetal and/or neonatal exposure, steroidogenic acute regulatory protein (StAR).

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Section: Discussionmentioning

confidence: 99%

Progression of the Dose-Related Effects of Estrogenic Endocrine Disruptors, an Important Factor in Declining Fertility, Differs between the Hypothalamo-Pituitary Axis and Reproductive Organs of Male Mice

Warita

Sugawara

Yue

et al. 2006

The Journal of Veterinary Medical Science

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“…On the other hand, detailed studies have not yet been performed with respect to StAR expression in the CNS. Northern blot analysis revealed StAR mRNA expression in some peripheral organs (kidney, testis, ovary, and adrenal gland) but not in the brain (Sugawara et al, 1995). However, taking into account the quite low level expression of cytochrome P-450 5~mRNA, the amount of the StAR transcript expressed in the brain may also be very small.…”

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confidence: 94%

Steroidogenic Acute Regulatory Protein (StAR) Transcripts Constitutively Expressed in the Adult Rat Central Nervous System: Colocalization of StAR, Cytochrome P‐450_SCC (CYP XIA1), and 3β‐Hydroxysteroid Dehydrogenase in the Rat Brain

Furukawa¹,

Miyatake

Ohnishi³

et al. 1998

Journal of Neurochemistry

214

173

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Steroidogenic acute regulatory protein (StAR) is a 30-kDa protein involved in the transport of cholesterol to the inner mitochondrial membrane and thus plays a key role in steroid biosynthesis. To clarify the implications of this protein in neurosteroid biosynthesis, we examined the possible expression of a StAR transcript in the adult rat CNS and detected it. cDNA cloning and sequencing analysis revealed that two forms of StAR mRNAs are expressed in the brain in the same manner as in the adrenal gland, indicating that they are fully functional and not minor gene transcripts. An RNase protection assay quantitatively revealed that the amount of the rat StAR transcript in brain was two to three orders of magnitude lower than that in the adrenal gland. An in situ hybridization study, involving antisense riboprobes, revealed that StAR transcripts were abundant in the cerebral cortex, hippocampus, dentate gyrus, olfactory bulb, cerebellar granular layer, and Purkinje cells. Furthermore, other steroidogenic enzymes, side-chain cleavage cytochrome P-45O~~(CYP XIA1) and 3/3-hydroxysteroid dehydrogenase/z~isomerase (EC 1.1.1 .145), were found tobe coexpressed in the hippocampus, dentate gyrus, cerebellar granular layer, and Purkinje cells. These findings strongly indicate that neurosteroids are synthesized in a region-specific manner in the brain. Key Words: Steroidogenic acute regulatory protein -Brain-Neurosteroid-In situ hybridization -Ribonuclease protection assay-Cholesterol side-chain cleavage enzyme.

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“…However, defects in P450scc, adrenodoxin, and adrenodoxin reductase were eliminated by molecular genetic analysis of affected patients (5)(6)(7). Recently, the gene for steroidogenic acute regulatory protein (StAR), which functions as a labile protein factor in steroidogenesis mediating cholesterol transport within mitochondria, was cloned (8)(9)(10). Mutations in the StAR gene were subsequently identified as the cause of lipoid CAH (8,11).…”

Section: Introductionmentioning

confidence: 99%

Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene.

Fukui¹,

Tajima²,

Nakae³

et al. 1997

J. Clin. Invest.

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145

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Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH in which the synthesis of all gonadal and adrenal cortical steroids is markedly impaired. We report here the clinical, endocrinological, and molecular analyses of two unrelated Japanese kindreds of 46,XX subjects affected with lipoid CAH who manifested spontaneous puberty. Phenotypic female infants with 46,XX karyotypes were diagnosed with lipoid CAH as newborns based on a clinical history of failure to thrive, hyperpigmentation, hyponatremia, hyperkalemia, and low basal values of serum cortisol and urinary 17-hydroxycorticosteroid and 17-ketosteroid. These patients responded to treatment with glucocorticoid and 9 ␣ -fludrocortisone. Spontaneous thelarche occurred in association with increased serum estradiol levels at the age of 10 and 11 yr, respectively. Pubic hair developed at the age of 12 yr 11 mo in one subject and menarche was at the age of 12 yr in both cases. Both subjects reported periodic menstrual bleeding and subsequently developed polycystic ovaries. To investigate the molecular basis of the steroidogenic lesion in these patients, the StAR gene was characterized by PCR and direct DNA sequence analyses. DNA sequence analysis revealed that one patient is homozygous for the Gln 258 Stop mutation in exon 7 and that the other patient is a compound heterozygote with the Gln 258 Stop mutation and a single A deletion at codon 238 in the other allele causing a frame-shift, which renders the StAR protein nonfunctional. These findings demonstrate that ovarian steroidogenesis can be spared to some extent through puberty when the StAR gene product is inactive. This is in marked contrast to the early onset of severe defects in testicular and adrenocortical steroidogenesis which are characteristics of this disease.

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Human steroidogenic acute regulatory protein: functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13.

Abstract: Steroidogenic acute regulatory protein (StAR) appears to mediate the rapid increase in pregnenolone synthesis stimulated by tropic hormones. cDNAs encoding StAR were isolated from a human adrenal cortex library.

Cited by 354 publications

References 31 publications

Progression of the Dose-Related Effects of Estrogenic Endocrine Disruptors, an Important Factor in Declining Fertility, Differs between the Hypothalamo-Pituitary Axis and Reproductive Organs of Male Mice

Progression of the Dose-Related Effects of Estrogenic Endocrine Disruptors, an Important Factor in Declining Fertility, Differs between the Hypothalamo-Pituitary Axis and Reproductive Organs of Male Mice

Steroidogenic Acute Regulatory Protein (StAR) Transcripts Constitutively Expressed in the Adult Rat Central Nervous System: Colocalization of StAR, Cytochrome P‐450_SCC (CYP XIA1), and 3β‐Hydroxysteroid Dehydrogenase in the Rat Brain

Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene.

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Human steroidogenic acute regulatory protein: functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13.

Abstract: Steroidogenic acute regulatory protein (StAR) appears to mediate the rapid increase in pregnenolone synthesis stimulated by tropic hormones. cDNAs encoding StAR were isolated from a human adrenal cortex library.

Cited by 354 publications

References 31 publications

Progression of the Dose-Related Effects of Estrogenic Endocrine Disruptors, an Important Factor in Declining Fertility, Differs between the Hypothalamo-Pituitary Axis and Reproductive Organs of Male Mice

Progression of the Dose-Related Effects of Estrogenic Endocrine Disruptors, an Important Factor in Declining Fertility, Differs between the Hypothalamo-Pituitary Axis and Reproductive Organs of Male Mice

Steroidogenic Acute Regulatory Protein (StAR) Transcripts Constitutively Expressed in the Adult Rat Central Nervous System: Colocalization of StAR, Cytochrome P‐450SCC (CYP XIA1), and 3β‐Hydroxysteroid Dehydrogenase in the Rat Brain

Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene.

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Steroidogenic Acute Regulatory Protein (StAR) Transcripts Constitutively Expressed in the Adult Rat Central Nervous System: Colocalization of StAR, Cytochrome P‐450_SCC (CYP XIA1), and 3β‐Hydroxysteroid Dehydrogenase in the Rat Brain