Elements involved in the regulation of the StAR gene

Stocco, Douglas M.; Clark, Barbara J.; Reinhart, Adam J.; Williams, Simon C.; Dyson, Matthew T.; Dassi, B.; Walsh, Lance P.; Manna, Pulak R.; Wang, XingJia; Zeleznik, Anthony J.; Orly, Joseph

doi:10.1016/s0303-7207(01)00423-3

Cited by 70 publications

(46 citation statements)

References 46 publications

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“…Since no precursor pool of StAR exists in the cell and the accumulation of StAR is cycloheximide-sensitive, these data suggest that StAR is translationally regulated. However, evidence for changes in the rate of StAR translation, especially in the early moments of hormonal stimulation, remains elusive ( Artemenko et al 2001, Clark et al 2001. Alternatively, oxysterols may simply reduce the degradation rate of non-functional mature StAR protein.…”

Section: Discussionmentioning

confidence: 99%

“…Oxysterol action may be essential for increasing steroid synthesis in the first minute of trophic hormone stimulation through translational regulation or stabilization of the active form of StAR (Clark & Combs 1999, Artemenko et al 2001, Clark et al 2001. The level of steroid consequently elicited may be appropriately small in order to be non-depleting, since cholesterol supply pathways are not activated by oxysterol (Javitt 2002).…”

Section: Discussionmentioning

confidence: 99%

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Oxysterols regulate expression of the steroidogenic acute regulatory protein

King¹,

Matassa²,

White³

et al. 2004

Journal of Molecular Endocrinology

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The steroidogenic acute regulatory (StAR) protein promotes intramitochondrial delivery of cholesterol to the cholesterol side-chain cleavage system, which catalyzes the first enzymatic step in all steroid synthesis. Intriguingly, substrate cholesterol derived from lipoprotein can upregulate StAR gene expression. Moreover, substrate oxysterols have been suggested to also play a role. To investigate whether oxysterols can regulate StAR expression, two steroidogenic cell lines, mouse Y1 adrenocortical and MA-10 Leydig tumor cells, were treated with various oxysterols and steroids, including 25-hydroxycholesterol (25 OHC), 22(R)OHC and 20 OHC. The majority of these compounds rapidly increased StAR protein levels within as little as 1 h. The most potent oxysterols were 20 OHC for Y1 and 25 OHC for MA-10 cells. After 8 h, StAR mRNA abundance also increased whereas there were no detected changes in promoter activity. Thus, in contrast to lipoprotein, oxysterols acutely increase StAR protein levels independently of mRNA abundance, and later increase mRNA levels independently of new gene transcription. Therefore, we propose that oxysterols modulate steroidogenesis at two levels. First, oxysterols may be important in post-transcriptional regulation of StAR activity and production of steroids for paracrine action. Secondly, through direct conversion to steroid, oxysterols may account in part for StAR-independent steroid production in the body.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Oxysterols regulate expression of the steroidogenic acute regulatory protein

King¹,

Matassa²,

White³

et al. 2004

Journal of Molecular Endocrinology

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“…6D). As for the site conferring cAMP responsiveness on the StAR gene, several investigations have been reported; accordingly, co-operative interaction between SF-1 bound to the proximal SF-1 site (9, 37) and other transcriptional factors bound to neighboring sites, such as the CCAAT/enhancer site (64,65) and GATA-4 site (66), have been thought to give the full activation of cAMPdependent as well as basal StAR promoter activity (67,68). Recently, SF-1 and CREB, or transcriptional factors belonging to its family, were implicated in the cAMP-activated mouse StAR promoter activity (42).…”

Section: Discussionmentioning

confidence: 99%

ACTH-induced Nucleocytoplasmic Translocation of Salt-inducible Kinase

Takemori¹,

Katoh²,

Horike³

et al. 2002

Journal of Biological Chemistry

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Salt-inducible kinase (SIK),Extracellular hormonal stimuli, received at the cell surface by the corresponding receptors, are transduced into several chemical messengers in the cytoplasm and regulate the transcription of genes in the nuclei. Adrenocorticotropic hormone (ACTH), 1 binding to its receptor on the adrenocortical cell surface, activates adenylate cyclase and increases intracellular cAMP, which in turn activates the cAMP-dependent protein kinase (PKA) (1-3). The activated PKA then promptly stimulates the biosynthesis and secretion of steroid hormone. This is achieved through stimulation of several intracellular events; PKA activates cholesterol esterases (4 -7), thus increasing the intracellular cholesterol pool, and elevates the levels of transcription (8, 9), mRNA stability (10), translation (8), and posttranslational modification (11-15) of the steroidogenic acute regulatory (StAR) protein (16). This accelerates the transport of cholesterol from the outer to inner mitochondrial membranes, which activates the side chain cleavage cytochrome P450 (CYP11A) reaction (17-21). The resultant elevation of the plasma glucocorticoid level acts as a negative signal on the ACTH secretion from the pituitary gland, thus completing the feedback regulatory loop of the hypothalamic-pituitary-adrenocortical axis (22, 23). Several signaling molecules (24 -30) other than those mentioned above, such as phosphodiesterase (31) and protein phosphatase (32) have also been implicated in regulating steroidogenesis, indicating that the steroidogenic cells are equipped with finely tuned signal transducing systems. However, the precise mechanism underlying the acute regulation of steroidogenic gene expression, including the molecular events occurring during the initiation, maintenance, and termination of the steroidogenic gene transcription, is as yet not well understood.Salt-inducible kinase (SIK) was identified as a serine/threonine protein kinase induced in the adrenal glands of high-salt diet-fed rats (33, 34). When Y1 mouse adrenocortical tumor cells were incubated with ACTH, the cellular levels of mRNA, protein, and kinase activity of SIK were elevated within 1 h through the cAMP/PKA signaling mechanism, and then after a few hours the levels declined (35). In contrast, the transcription of StAR and CYP11A genes begin later, at a time coinciding * This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and Ministry of Health, Labor and Welfare Japan and grants from The Uehara Memorial Foundation and from The Ichiro Kanehara Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.□ S The on-line version of this article (available at http://www.jbc.org) contains two supplemental figures.ʈ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular B...

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“…Steroidogenesis is regulated by steroidogenic enzymes, including the steroidogenic acute regulatory protein (StAR), the cholesterol side chain cleavage enzyme (P450scc), 17␣-hydroxylase/C17-20 lyase (P450c17), 3␤-hydroxysteroid dehydrogenase (3␤-HSD), DAX-1, and Nur77 (7)(8)(9)(10)(11)(12)(13). It is well known that cAMP regulates the expression of steroidogenic enzymes in Leydig cells through a variety of transcription factors, including steroidogenic factor-1 (SF-1), DAX-1, CCAAT/ enhancer-binding protein-␤, liver receptor homolog-1 (LRH-1), Nur77, and the CREB protein (9 -14).…”

mentioning

confidence: 99%

“…It is well known that cAMP regulates the expression of steroidogenic enzymes in Leydig cells through a variety of transcription factors, including steroidogenic factor-1 (SF-1), DAX-1, CCAAT/ enhancer-binding protein-␤, liver receptor homolog-1 (LRH-1), Nur77, and the CREB protein (9 -14). cAMP signaling regulates StAR gene expression and steroidogenesis via CREB activation (11,12). DAX-1, a negative regulator of orphan nuclear receptors, decreases StAR gene expression by inhibiting CREB transcriptional activity in Leydig cells (15).…”

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confidence: 99%