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.05. Results StAR cloning and sequencing A gilthead seabream ( S. aurata ) cDNA library made in λ ZAP Express III (Stratagene) from several relevant immune sources was used to clone the steroidogenic acute regulatory protein, StAR (GenBank accession
Department of Zoology, University of Otago, PO Box 56, Dunedin, New Zealand
Northwest Fisheries Science Center, NOAA Fisheries, Seattle, Washington 98112, USA
Center for Reproductive Biology, Washington State University, Pullman, Washington 99164, USA
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Department of Zoology, University of Otago, PO Box 56, Dunedin, New Zealand
Northwest Fisheries Science Center, NOAA Fisheries, Seattle, Washington 98112, USA
Center for Reproductive Biology, Washington State University, Pullman, Washington 99164, USA
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Department of Zoology, University of Otago, PO Box 56, Dunedin, New Zealand
Northwest Fisheries Science Center, NOAA Fisheries, Seattle, Washington 98112, USA
Center for Reproductive Biology, Washington State University, Pullman, Washington 99164, USA
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Department of Zoology, University of Otago, PO Box 56, Dunedin, New Zealand
Northwest Fisheries Science Center, NOAA Fisheries, Seattle, Washington 98112, USA
Center for Reproductive Biology, Washington State University, Pullman, Washington 99164, USA
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Department of Zoology, University of Otago, PO Box 56, Dunedin, New Zealand
Northwest Fisheries Science Center, NOAA Fisheries, Seattle, Washington 98112, USA
Center for Reproductive Biology, Washington State University, Pullman, Washington 99164, USA
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the rate of the delivery of cholesterol to P450scc by steroidogenic acute regulatory protein (StAR) ( Stocco 2000 ). Studies on mammalian StARs have mainly concentrated on the short-term (acute) changes in steroidogenesis with little information
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Abstract
The steroidogenic acute regulatory protein (StAR) has recently been shown to be a factor necessary for cholesterol transport into adrenal and gonadal mitochondria, which is the regulated, rate-limiting step in steroidogenesis. We show here that StAR mRNA is highly expressed in normal adult adrenals (n=9), adrenocortical adenomas (n=16), adrenal hyperplasias (n=6), adrenocortical carcinomas (n=6) and adrenals adjacent to tumor tissues (n=9). There was a good correlation between the expression of StAR and the cholesterol side-chain cleavage enzyme/20,22-desmolase (P450 scc) mRNAs both in normal (r=0·93; P<0·01) and in tumor (r=0·97; P<0·001) tissues. No StAR mRNA was detected in Northern blots of liver, kidney, breast, parathyroid or phaeochromocytoma RNAs.
In cultured adrenocortical cells, adrenocorticotropin (ACTH), (Bu)2cAMP, and cholera toxin increased StAR and P450 scc mRNA accumulation 6- to 18-fold, dose-and time-dependently. StAR (and P450 scc) mRNA increased relatively slowly in response to ACTH treatment, with the maximal increment at 24 h, while the mRNA of the early response gene c-fos peaked within 2 h. The protein kinase inhibitor H-7 inhibited basal and ACTH-induced StAR mRNA expression. Our results show that StAR mRNA is expressed at high levels in normal human adrenals and adrenocortical neoplasms. It is up-regulated in parallel with P450 scc by ACTH in adult adrenocortical cells, which suggests that ACTH is at least one of the key regulators of adrenal StAR expression.
Journal of Endocrinology (1996) 150, 43–50
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The purpose of this investigation was to study the mechanism of action of a macrophage-derived factor that stimulates steroid production by Leydig cells. This factor increased testosterone production within 30 min, and reached a half-maximal response by 6-8 h. At a maximal dose, it stimulated testosterone production 20-fold at 24 h. Its efficacy was consistently higher than that achieved with a maximal dose of human chorionic gonadotropin (hCG). However, Leydig cells treated with a maximal dose of both the macrophage-derived factor and hCG secreted the same amount of testosterone as when given a maximal dose of only the macrophage-derived factor. The macrophage-derived factor did not require new protein synthesis to stimulate testosterone production, nor did it alter the amount of steroidogenic acute regulatory protein (StAR). While the macrophage-derived factor required an active cholesterol side-chain cleavage complex system, it did not alter the capacity of this enzyme complex. Finally, the macrophage-derived factor was unable to stimulate the production of progesterone by isolated mitochondria. In summary, the macrophage-derived factor is a highly active, acute regulator of steroidogenesis that acts through a high capacity StAR-independent pathway.
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The rate-limiting step of steroidogenesis is the transport of the substrate cholesterol from the outer to the inner mitochondrial membrane which involves a cycloheximide-sensitive newly synthesized protein. A protein believed to carry out this function was recently cloned from MA-10 mouse Leydig tumor cells and named the steroidogenic acute regulatory protein (StAR). In the present study, we evaluated the expression and regulation of StAR in primary cultures of rat Leydig cells. StAR mRNA was expressed in Leydig cells as two major transcripts of 3.8 and 1.7 kb and one minor transcript of 1.2 kb. Induction of StAR mRNA transcripts could be detected as early as 30 min after the addition of human choriogonadotropin (hCG) with peak levels attained between 2 and 4 h. hCG in concentrations of 0.1-10 ng/ml caused a dose-dependent increase in StAR mRNA expression. hCG administered at a dose of 10 ng/ml increased the 3.8 kb StAR mRNA level about 14-fold and the 1.7 kb StAR mRNA level about 13.6-fold. hCG-stimulated StAR mRNA was associated with increased StAR protein levels as determined by immunoblot analysis (a 4.5-fold increase). Murine interleukin-1 alpha (mIL-1 alpha) at a concentration of 100 ng/ml inhibited hCG-induced cytochrome P450 side-chain cleavage (P450 scc) mRNA expression and testosterone formation almost completely. Interestingly, mIL-1 alpha had no effect on hCG-induced StAR mRNA or protein levels. Furthermore, mIL-1 alpha (10 ng/ml) decreased conversion of (22R)-hydroxycholesterol to testosterone while the conversion of pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone and androstenedione to testosterone were not affected. These results indicate that the major inhibitory effect of IL-1 on Leydig cell function occurs at the level of P450 scc.
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‘CholesteROR’ protective pathway in the vascular system . Arteriosclerosis, Thrombosis, and Vascular Biology 24 637 – 643 . Christenson LK Strauss JF III 2000 Steroidogenic acute regulatory protein (StAR) and the intramitochondrial translocation of
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– 95 . Bose HS Whittal RM Baldwin MA Miller WL 1999 The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule . PNAS 96 7250 – 7255 . Brown GA Vukovich MD Martini ER Kohut ML Franke WD Jackson
Cell Biology and Biochemistry,
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Pathology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA
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Cell Biology and Biochemistry,
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Pathology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA
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Cell Biology and Biochemistry,
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Pathology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA
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Cell Biology and Biochemistry,
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Pathology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA
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Cell Biology and Biochemistry,
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Cell Biology and Biochemistry,
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Cell Biology and Biochemistry,
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luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). Journal of Biological Chemistry 269 28314 –28322. Cooke BA 1999
Obstetrics and Gynaecology, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 15, Nishi 7, Hokkaido, Sapporo 060-8638, Japan
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Obstetrics and Gynaecology, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 15, Nishi 7, Hokkaido, Sapporo 060-8638, Japan
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Obstetrics and Gynaecology, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 15, Nishi 7, Hokkaido, Sapporo 060-8638, Japan
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& Strauss JF III 1997 Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity. Journal of Biological Chemistry 272 32656 –32662. Bannister AJ & Kouzarides T 1995 CBP
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Department of BioMedical Research, University of Bern, Bern, Switzerland
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Introduction Steroidogenic acute regulatory protein (STAR/STARD1) was identified 3 decades ago in adrenal and gonadal tissues ( Clark et al. 1994 ). It was shown to mediate the fast response of pregnenolone synthesis upon tropic hormone
