| steroidogenic acute regulatory protein | OKDB#: 316 |
| Symbols: | STAR | Species: | human | ||
| Synonyms: | STARD1 | Locus: | 8p11.23 in Homo sapiens |
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| General Comment |
In response to trophic hormone stimulation of steroidogenic adrenal and gonadal cells, the acute biosynthesis of steroid hormones occurs in the order of minutes to tens of minutes and can be contrasted to chronic regulation, which
occurs on the order of hours. The steroidogenic acute regulatory (StAR) protein is an indispensable component in the acute regulatory phase and functions by rapidly mediating the transfer of the substrate for all steroid hormones, cholesterol, from the outer to the inner mitochondrial membrane where it is cleaved to pregnenolone, the first steroid formed (Stocco, 1999). The STAR transcripts have been detected in the ovary and testis as well as the kidney. STAR mRNA has not been found in other tissues. It has been concluded that STAR expression is restricted to tissues that carry out mitochondrial sterol oxidations subject to acute regulation by cAMP.
Gene expression increased. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression. Agca C et al.
NCBI Summary: The protein encoded by this gene plays a key role in the acute regulation of steroid hormone synthesis by enhancing the conversion of cholesterol into pregnenolone. This protein permits the cleavage of cholesterol into pregnenolone by mediating the transport of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane. Mutations in this gene are a cause of congenital lipoid adrenal hyperplasia (CLAH), also called lipoid CAH. A pseudogene of this gene is located on chromosome 13. [provided by RefSeq, Jul 2008] |
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| General function | Metabolism, Enzyme | ||||
| Comment | StAR mediates the transfer of cholesterol in the cell, from the outer to the inner membrane of the mitochondria, during the process of cholesterol metabolism (Stocco, 1999). The StAR protein has two key functional domains. The StAR C-terminal domain increases cholesterol movement to cytochrome P450scc by promoting sterol desorption from the sterol-rich outer mitochondrial membrane, driving it to the relatively sterol-poor inner membrane. The N-terminal domain mitochondrial targeting sequence directs the StAR protein to the mitochondria.Strauss J 3rd, et al 1999 | ||||
| Cellular localization | Mitochondrial | ||||
| Comment | The steroidogenic acute regulatory (StAR) protein is an indispensable component in the acute regulatory phase and functions by rapidly mediating the transfer of the substrate for all steroid hormones, cholesterol, from the outer to the inner mitochondrial membrane where it is cleaved to pregnenolone, the first steroid formed (Stocco, 1999). | ||||
| Ovarian function | Steroid metabolism, Luteinization | ||||
| Comment | Congenital lipoid adrenal hyperplasia is an autosomal recessive disorder that is characterized by impaired synthesis of all adrenal and gonadal steroid hormones. In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional, providing genetic evidence that this protein is indispensable normal adrenal and gonadal steroidogenesis (Lin et al., 1995). | ||||
| Expression regulated by | FSH, LH, Growth Factors/ cytokines, cAMP, Clock, Bmal1 | ||||
| Comment | Changes in Histone Modification and DNA Methylation of the StAR and Cyp19a1 Promoter Regions in Granulosa Cells Undergoing Luteinization during Ovulation In Rats. Lee L et al. The ovulatory LH surge induces rapid up-regulation of steroidogenic acute regulatory (StAR) protein and rapid down-regulation of aromatase (Cyp19a1) in granulosa cells (GCs) undergoing luteinization during ovulation. This study investigated in vivo whether epigenetic mechanisms including histone modifications are involved in the rapid changes of StAR and Cyp19a1 gene expression. GCs were obtained from rats treated with equine chorionic gonadotropin (CG) before (0 h) and after human (h)CG injection. StAR mRNA levels rapidly increased after hCG injection, reached a peak at 4 h, and then remained higher compared with 0 h until 12 h. Cyp19a1 mRNA levels gradually decreased after hCG injection and reached their lowest level at 12 h. A chromatin immunoprecipitation assay revealed that levels of histone-H4 acetylation (Ac-H4) and trimethylation of histone-H3 lysine-4 (H3K4me3) increased whereas H3K9me3 and H3K27me3 decreased in the StAR promoter after hCG injection. On the other hand, the levels of Ac-H3 and -H4 and H3K4me3 decreased, and H3K27me3 increased in the Cyp19a1 promoter after hCG injection. Chromatin condensation, which was analyzed using deoxyribonuclease I, decreased in the StAR promoter and increased in the Cyp19a1 promoter after hCG injection. A chromatin immunoprecipitation assay also showed that binding activities of CAATT/enhancer-binding protein ?to the StAR promoter increased and binding activities of phosphorylated-cAMP response element binding protein to the Cyp19a1 promoter decreased after hCG injection. These results provide in vivo evidence that histone modifications are involved in the rapid changes of StAR and Cyp19a1 gene expression by altering chromatin structure of the promoters in GCs undergoing luteinization during ovulation. Transcription of Steroidogenic Acute Regulatory protein (STAR) in the rodent ovary and placenta: alternative modes of cyclic adenosine 3', 5'-monophosphate dependent and independent regulation. Yivgi-Ohana N et al. Steroid hormone synthesis is a vital function of the adrenal cortex, serves a critical role in gonadal function, and maintains pregnancy if normally executed in the placenta. The substrate for the synthesis of all steroid hormones is cholesterol and its conversion to the first steroid, pregnenolone, by the cholesterol side chain cleavage cytochrome P450 (CYP11A1, P450scc) enzyme complex takes place in the inner mitochondrial membranes. Steroidogenic acute regulatory protein (STAR) facilitates the rate limiting transfer of cholesterol from the outer mitochondrial membrane to P450scc located in the inner organelle membranes. The current study explored the mechanisms controlling transcription of the star gene in primary cell cultures of mouse placental trophoblast giant (TG) cells and rat ovarian granulosa cells examined throughout the course of their functional differentiation. Our findings show that the cis-elements required for star transcription in the rodent placenta and the ovary are centered in a relatively small proximal region of the promoter. In placental TG cells, cAMP is required for activation of the star promoter and the cis-elements mediating a maximal response were defined as cAMP Response Element 2 (CRE2) and GATA. EMSA studies show that placental CREB-1 and ATF-2 bind to a -81/-78 sequence, while GATA-2 binds to a -66/-61 sequence. In comparison, patterns of star regulation in the ovary suggested tissue-specific and developmental controlled modes of star transcription: during the follicular phase, FSH/cAMP induced CREB-1 dependent activity, while upon luteinization STAR expression becomes cAMP and CREB independent, a functional shift conferred by FRA-2 displacement of CREB-1 binding and the appearance of a new requirement for C/EBPbeta and SF-1 that bind to upstream elements (-117/-95). These findings suggest that during evolution the promoters of the star gene acquired non-consensus sequence elements enabling expression of a single gene in different organs, or allowing dynamic temporal changes corresponding to progressing phases of differentiation in a given cell type. StAR expression is restricted to tissues that carry out mitochondrial sterol oxidations subject to acute regulation by cAMP and StAR mRNA levels are regulated by cAMP (Sugawara et al., 1995). Devoto L, et al 2001 reported the expression of steroidogenic acute regulatory protein in the human corpus luteum throughout the luteal phase. The primary 1.6-kb SCAR transcript was in greater abundance in early (3.1-fold) and mid (2.2-fold) luteal phase CL compared with late luteal phase CL. The larger StAR transcript (4.4 kb) was found in early and midluteal phase CL, but was not detected in late luteal phase specimens. Mature StAR protein (30 kDa) was present in lower amounts within late CL compared with early and midluteal phase CL. The StAR preprotein (37 kDa) was also detected in greater abundance in early and midluteal CL. Immunohistochemistry revealed that StAR staining was most prominent in thecal-lutein cells throughout the luteal phase. To examine the LH dependency of SCAR expression, the GnRH antagonist, Cetrorelix, was administered during the midluteal phase. Cetrorelix caused a decline in serum LH levels within 2 h, which, in turn, caused a pronounced decline in plasma progesterone within 6 h. The StAR 4.4-kb transcript was not detectable, and the 1.6-kb transcript was reduced by approximately 50% within 24 h of Cetrorelix treatment. The mature 30-kDa StAR protein level declined approximately 30% after Cetrorelix treatment. Thus, 1) StAR mRNA and protein are highly expressed in early and midluteal phase CL; 2) StAR protein is present in both thecal-lutein and granulosa-lutein cells throughout the luteal phase; 3) StAR protein levels in the CL are highly correlated with plasma progesterone levels; 4) declining StAR mRNA and protein levels are characteristic of late luteal phase CL; and 5) suppression of LH levels during the midluteal phase results in a marked decline in plasma progesterone and a diminished abundance of StAR transcripts in the CL without a corresponding significant decline in StAR protein. Collectively, these data are consistent with the idea that StAR gene expression is a key determinant of luteal progesterone during the normal menstrual cycle. However, the pharmacologically induced withdrawal in the midluteal phase of LH support diminishes luteal progesterone output by mechanisms others than reduced SCAR protein levels: Gene expression decreased. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression. Agca C et al. The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and structural changes that ultimately lead to ovulation and the formation of corpora lutea. The objective of the study was to examine gene expression in ovarian follicles (n = 11) collected from pigs (Sus scrofa domestica) approaching estrus (estrogenic preovulatory follicle; n = 6 follicles from two sows) and in ovarian follicles collected from pigs on the second day of estrus (preovulatory follicles that were luteinized but had not ovulated; n = 5 follicles from two sows). The follicular status within each follicle was confirmed by follicular fluid analyses of estradiol and progesterone ratios. Microarrays were made from expressed sequence tags that were isolated from cDNA libraries of porcine ovary. Gene expression was measured by hybridization of fluorescently labeled cDNA (preovulatory estrogenic or -luteinized) to the microarray. Microarray analyses detected 107 and 43 genes whose expression was decreased or increased (respectively) during the transition from preovulatory estrogenic to -luteinized (P<0.01). Cells within preovulatory estrogenic follicles had a gene-expression profile of proliferative and metabolically active cells that were responding to oxidative stress. Cells within preovulatory luteinized follicles had a gene-expression profile of nonproliferative and migratory cells with angiogenic properties. Approximately, 40% of the discovered genes had unknown function. Circadian clock gene regulation of steroidogenic acute regulatory protein gene expression in pre-ovulatory ovarian follicles. Nakao N et al. It is now known that circadian clocks are localized not only in the central pacemaker but also in peripheral organs. An example of a clock-dependent peripheral organ is the ovary of domestic poultry where ovulation is induced by the positive feed-back action of ovarian progesterone on the neuroendocrine system to generate a pre-ovulatory release of LH during a daily 6-10 hr 'open period' of the ovulatory cycle. It has previously been assumed that the timing of ovulation in poultry is controlled solely by a clock-dependent mechanism within neuroendocrine system. Here, we question this assumption by demonstrating the expression of the clock genes, Per2 and 3, Clock and Bmal1 in pre-ovulatory follicles in laying quail. Diurnal changes in Per2 and 3 expression were seen in the largest pre-ovulatory follicle (F1), but not in smaller follicles. We next sought to identify clock-driven genes in pre-ovulatory follicles focusing on those involved in the synthesis of progesterone. One such gene was identified, encoding steroidogenic acute regulatory protein (StAR), which showed 24 hr changes in expression in the F1 follicle coinciding with those of Per2. Evidence that StAR gene expression is clock-driven was obtained by showing that its 5' flanking region contains E-box enhancers, which bind to CLOCK/BMAL1 heterodimers to activate gene transcription. We also showed that LH administration increased the promoter activity of chicken StAR. We therefore suggest that the timing of ovulation in poultry involves a LH- responsive F1 follicular clock that is involved in the timing of the pre-ovulatory release of progesterone. | ||||
| Ovarian localization | Granulosa, Theca, Luteal cells | ||||
| Comment | Insulin and insulin-like growth factors (IGF)-I and -II stimulate granulosa cell steroidogenesis. Since steroidogenic acute regulatory protein (StAR) regulates the rate-limiting step in steroid hormone biosynthesis, the ability of insulin and IGF to modulate StAR protein and mRNA expression was examined in two human granulosa cell culture systems: (i) proliferating granulosa-lutein cells and (ii) luteinized-granulosa cells derived during in-vitro fertilization (IVF) (Devoto et al., 1999). In the bovine: To examine hormonal regulation of genes pertinent to luteal steroidogenesis, bovine theca and granulosa cells derived from preovulatory follicles were cultured with various combinations of forskolin and insulin (Mamluk et al., 1999). In the rat: Using specific antisera against the StAR, immunohistochemistry, Western blotting, and immunoprecipitation analyses provide evidence confirming the localization and expression of StAR in granulosa cells (GCs) of juvenile rat ovaries before and after PMSG treatment. The results also show that StAR expression occurs in theca intersitial cells surrounding preantral, antral, and larger antral follicles in adult diestrous ovaries. Furthermore, we have demonstrated heterogenous StAR immunoreactivity in the granulosa cell layers and cells of the corpora lutea. (Thompson et al., 1999). Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization. | ||||
| Follicle stages | Primary, Secondary, Antral, Preovulatory, Corpus luteum | ||||
| Comment | This study was designed to determine the pattern of expression and cellular distribution of the steroidogenic acute regulatory protein (StAR) during the transitional stages of follicular differentiation in rat ovary. Using specific antisera against the StAR, immunohistochemistry, Western blotting, and immunoprecipitation analyses provide evidence confirming the localization and expression of StAR in granulosa cells (GCs) of juvenile rat ovaries before and after PMSG treatment. The results also show that StAR expression occurs in theca intersitial cells surrounding preantral, antral, and larger antral follicles in adult diestrous ovaries. A novel finding presented here is that, during ongoing growth and differentiation of the follicle, the immunoreactivity of StAR tends to shift from the GC of early antral follicles to the theca cell layers in the adult. The spatiotemporal changes or shifts in StAR expression and cellular localization also coincide with the appearance of more acidic isoforms of the 30-kD protein, as determined by two-dimensional gel electrophoresis. Although the functional implications of these observations remain unclear, the acute temporal changes in StAR expression and localization may not only reflect the dynamic steroidogenic capacity of follicular cells but may also support a possible role for FSH in the induction of follicular maturation (Thompson et al., 1999). | ||||
| Phenotypes |
POF (premature ovarian failure) |
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| Mutations |
4 mutations
Species: mouse
Species: human
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | Dec. 8, 1999, midnight | by: |
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| last update: | March 29, 2020, 3:11 p.m. | by: | hsueh email: |
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