Role of Steroidogenic Acute Regulatory Protein in Adrenal and Gonadal Steroidogenesis

Lin, Dong; Sugawara, Teruo; Strauss, Jerome F.; Clark, Barbara J.; Stocco, Douglas M.; Saenger, Paul; Rogol, Alan D.; Miller, Walter L.

doi:10.1126/science.7892608

Cited by 947 publications

(592 citation statements)

References 16 publications

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“…However, if the mutated residues are not conserved between these proteins, steroidogenic activity is retained. The findings on the new mutations in the present study are consonant with the recent genetic analysis of congenital lipoid adrenal hyperplasia (3,4,10,15). Mutations that truncate the C terminus of StAR destroy the functional activity of StAR, and all known mutations that cause amino acid replacements that inactivate the protein are clustered in exons 5-7, which encode the StAR C terminus.…”

Section: Discussionsupporting

confidence: 62%

“…COS-1 cells were transfected with the plasmid expressing the cholesterol sidechain cleavage enzyme and the plasmids expressing MLN64, MLN64 mutants, human wild-type StAR or StAR mutants, or the empty vectors by using Lipofectamine as previously described (3,4,6). Cultures were incubated in the absence or presence of ͑22R͒-22-hydroxycholesterol (5 g͞ml) for 36 h. Pregnenolone production was determined by radioimmunoassay using an antibody kindly provided by Charles Strott (National Institutes of Health) (6).…”

Section: Methodsmentioning

confidence: 99%

“…In the adrenal cortex and gonads, the translocation of cholesterol substrate to P450scc is under the control of corticotropin (ACTH) and luteinizing hormone (LH), respectively, through the intermediacy of the steroidogenic acute regulatory protein (StAR) (2). Individuals who are homozygous for mutations that inactivate StAR have a marked impairment in adrenal and gonadal steroidogenesis (3,4). The C-terminal domains of StAR are essential for its steroidogenic activity, since deletion of C-terminal sequences, but not Nterminal sequences, ablates steroidogenesis-enhancing activity (5).…”

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confidence: 99%

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MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis

Watari¹,

Arakane²,

Moog-Lutz³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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222

154

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MLN64 is a protein that is highly expressed in certain breast carcinomas. The C terminus of MLN64 shares significant homology with the steroidogenic acute regulatory protein (StAR), which plays a key role in steroid hormone biosynthesis by enhancing the intramitochondrial translocation of cholesterol to the cholesterol side-chain cleavage enzyme. We tested the ability of MLN64 to stimulate steroidogenesis by using COS-1 cells cotransfected with plasmids expressing the human cholesterol side-chain cleavage enzyme system and wild-type and mutant MLN64 proteins. Wild-type MLN64 increased pregnenolone secretion in this system 2-fold. The steroidogenic activity of MLN64 was found to reside in the C terminus of the protein, because constructs from which the C-terminal StAR homology domain was deleted had no steroidogenic activity. In contrast, removal of N-terminal sequences increased MLN64's steroidogenesisenhancing activity. MLN64 mRNA was found in many human tissues, including the placenta and brain, which synthesize steroid hormones but do not express StAR. Western blot analysis revealed the presence of lower molecular weight immunoreactive MLN64 species that contain the C-terminal sequences in human tissues. Homologs of both MLN64 and StAR were identified in Caenorhabditis elegans, indicating that the two proteins are ancient. Mutations that inactivate StAR were correlated with amino acid residues that are identical or similar among StAR and MLN64, indicating that conserved motifs are important for steroidogenic activity. We conclude that MLN64 stimulates steroidogenesis by virtue of its homology to StAR.

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Section: Discussionsupporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis

Watari¹,

Arakane²,

Moog-Lutz³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

222

154

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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.

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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“…Additionally, strong evidence for the key role of StAR protein in the intramitochondrial cholesterol translocation has been provided by studies on patients with lipoid congenital adrenal hyperplasia, a genetic disease which results in a complete inability to synthesize steroids. Lin and co-workers have demonstrated that this lethal condition is caused by nonsense mutations in the gene for StAR which generate truncated and non-functional proteins (9). However, the molecular mechanism whereby StAR is able to effect the intramitochondrial cholesterol transfer still remains unknown.…”

Section: Vol 45 No 1 1998mentioning

confidence: 99%

Hormone‐induced changes in cardiolipin from leydog cells: Possible involvement in intramitochondrial cholesterol translocation

et al. 1998

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SUMMARY : The rate-limiting and hormonally regulated step in steroid hormone biosynthesis is the delivery of cholesterol from the outer to the inner mitochondrial membrane where cytochrome P450scc resides. Although the exact mechanism of intramitochondrial cholesterol translocation remains unknown, the formation of contact sites between outer and inner mitochondrial membranes appears as a necessary component for cholesterol transfer. Several pieces of evidence suggest that local formation of intermembrane contact is a consequence of a non-bilayer arrangement of polymorphic lipids which are enriched in the junctions. As a step toward clarifying mitochondrial contact sites formation and thus cholesterol translocation in steroidogenic cells, we have undertaken studies to identify the factors which might result in non-bilayer structure to be adopted by mitochondrial phospholipids on stimulation of MA-10 Leydig cells. Our results demonstrate that an increase in the unsaturation of the cardiolipin acyl groups on hormonal stimulation might favor the formation of non-bilayer adhesion points.

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Role of Steroidogenic Acute Regulatory Protein in Adrenal and Gonadal Steroidogenesis

Cited by 947 publications

References 16 publications

MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis

MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis

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.

Hormone‐induced changes in cardiolipin from leydog cells: Possible involvement in intramitochondrial cholesterol translocation

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