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Department of BioMedical Research, University of Bern, Bern, Switzerland
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Department of BioMedical Research, University of Bern, Bern, Switzerland
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
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Department of BioMedical Research, University of Bern, Bern, Switzerland
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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
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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Wells, S R King and D M Stocco eventually identified this protein and named it steroidogenic acute regulatory protein (StAR) in a manuscript published on November 11, 1994, in Journal of Biological Chemistry ( Clark et al. 1994 ). The group’s finding
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The steroidogenic acute regulatory or StAR protein has been shown to be instrumental in the acute regulation of steroid hormone biosynthesis through its action in mediating cholesterol transfer to the inner mitochondrial membrane and the cholesterol side chain cleavage enzyme system. Since the time of its cloning in 1994, a number of studies have been performed which underscore the important role that this protein plays in steroidogenesis. While it is now quite apparent that StAR fulfills the criteria for the acute regulator as proposed by early studies, several crucial areas remain poorly understood. This list is topped by the so far intractable nature of the mechanism of action of StAR in transferring cholesterol to the P450scc enzyme. A second area which should prove to be of great interest is that of further understanding the regulation of the StAR gene which, like many genes, is quite complex. Lastly, with the recent demonstration of StAR being present in the brain, determining if StAR has a role in the synthesis of neurosteroids should prove to be of great importance.
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Dimethoate is a widely used organophosphate insecticide that has been shown to disrupt reproductive function in animals. Although the pathogenesis of Dimethoate-induced reproductive toxicity remains to be determined, a reduction in serum testosterone levels is thought to play an important role in the development of Dimethoate-induced infertility. Since Leydig cells play a crucial role in male reproductive function by producing testosterone, the mouse MA-10 Leydig tumor cell line was used to determine if Dimethoate can directly block steroid hormone biosynthesis and to identify the site of steroidogenic inhibition. Dimethoate inhibited steroidogenesis in both a dose- and time-dependent manner without affecting total protein synthesis or protein kinase A activity. While it decreased the activity of the P450 side chain cleavage (P450 scc) enzyme, a reduction in the activity of this enzyme alone could not account for the level of Bu(2)cAMP-inhibited progesterone production. Instead, our results suggest that Dimethoate inhibited steroidogenesis primarily by blocking transcription of the steroidogenic acute regulatory (StAR) gene. This finding is significant since StAR protein mediates the rate-limiting and acutely-regulated step in steroidogenesis, the transfer of cholesterol from the outer to the inner mitochondrial membrane. This study indicates that StAR may be an important target for environmental pollutants which disrupt steroidogenesis and impair reproductive function.
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The LH signal transduction pathway features the activation of protein tyrosine phosphatases (PTPs) as one of the components of a cascade that includes other well characterized events such as cAMP-dependent protein kinase A (PKA) activation. Moreover, the action of PTPs is required to increase the rate-limiting step in steroid biosynthesis, namely the cAMP-regulated transfer of cholesterol to the inner mitochondrial membrane. Since both PKA activity and steroidogenic acute regulatory (StAR) protein induction are obligatory steps in this transfer of cholesterol, the present study was performed to investigate the role of PTPs in the regulation of PKA activity and StAR expression in response to LH/chorionic gonadotropin (CG) and 8Br-cAMP in MA-10 cells. While the exposure of MA-10 cells to the PTP inhibitor, phenylarsine oxide (PAO), did not modify PKA activity, it partially inhibited the effect of human CG and cAMP analog on StAR protein levels. Time-course studies demonstrated that PAO inhibited cAMP induction of StAR protein and mRNA. At 30 min, the effect on cAMP-stimulated StAR protein levels was a 35% inhibition, progressing to up to 90% inhibition at 120 min of stimulation. The maximal inhibitory effect on cAMP-induced StAR mRNA level was obtained at 60 min (85%). In summary, these results demonstrate that inhibition of PTP activity affected both StAR protein and mRNA synthesis and suggest that the activity of hormone-regulated PTPs is a requirement in the LH signaling cascade that results in the up-regulation of StAR protein and, subsequently, increased steroid synthesis.
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The steroidogenic acute regulatory (STAR) protein is an essential cholesterol transporter that shuttles cholesterol from the outer to the inner mitochondrial membrane in the major steroidogenic endocrine organs. It is a key player in the acute regulation of steroid hormone biosynthesis in response to tropic hormone stimulation. Its discovery thirty years ago sparked immediate interest in understanding how STAR action is controlled. Since increased STAR gene expression is a classic feature of the acute regulation of steroidogenesis, a special emphasis was placed on defining the transcriptional regulatory mechanisms that underlie its rapid induction in response to tropic hormone stimulation. These mechanisms include the effects of enhancers, the regulation of chromatin accessibility, the impact of epigenetic factors, and the role of transcription factors. Over the past three decades, understanding the transcription factors that regulate STAR gene expression has been the subject of more than 170 independent scientific publications making it one of, and if not the best, studied genes in the steroidogenic pathway. This intense research effort has led to the identification of dozens of transcription factors and their related binding sites in STAR 5' flanking (promoter) sequences across multiple species. STAR gene transcription appears to be complex in that a large number of transcription factors have been proposed to interact with either isolated or overlapping regulatory sequences that are tightly clustered over a relatively short promoter region upstream of the STAR transcription start site. Many of these transcription factors appear to work in unique combinatorial codes and are impacted by diverse hormonal and intracellular signaling pathways. This review provides a retrospective overview on the transcription factors proposed to regulate both basal and acute (hormonal) STAR gene expression, and how insights in this area have evolved over the past thirty years
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Danone Nutricia Research, Singapore, Republic of Singapore
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Department of Pediatrics, University Medical Centre Groningen, Groningen, The Netherlands
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Institute of Molecular and Cell Biology, A*STAR, Singapore, Republic of Singapore
School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
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and Research (A*STAR), adhering to the National Advisory Committee on Laboratory Animal Research guidelines. Experiments were performed in an Assessment and Accreditation of Laboratory Animal Care accredited specific pathogen free (SPF) facility
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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membranes contain phospholipids, and the inter-membrane space is an aqueous space. Cholesterol is hydrophobic and requires some factors to pass through the aqueous inter-membrane space. Steroidogenic acute regulatory (StAR) protein is a 30 kDa phosphorylated
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step of steroidogenesis in mammals is the availability of substrate for P450SCC and the steroidogenic acute regulatory (StAR) protein that plays a crucial role in steroidogenesis by transferring hydrophobic cholesterol across the aqueous barrier between
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). Since the intermembrane space of mitochondria is hydrophilic, a transport system is needed for the entry of cholesterol into the inner membrane, where P450scc resides. Steroidogenic acute regulatory (StAR) protein, which mediates the rate-limiting step
