Disease relevance of STAR

• Unlike our findings in CV-1 cells, SF-1-dependent StAR promoter activity was not augmented by 27-OHC in COS-1 cells, Y-1 cells, BeWo choriocarcinoma cells, Chinese hamster ovary (CHO) cells, and human granulosa cells [1].
• Half-maximum stimulation required more than a 10-fold higher concentration of R182L N-62 StAR, a mutant associated with congenital lipoid adrenal hyperplasia [2].
• Adrenal cortical adenomas, hyperplasias, and carcinomas all contained areas of StAR staining [3].
• Ovarian adenocarcinomas, borderline tumors, teratomas, cystadenomas, and a Brenner tumor displayed no specific StAR immunostaining [3].
• Steroidogenic acute regulatory protein (StAR) regulates the first committed step in the biosynthesis of steroids, and thus aberrant expression of StAR in endometriotic implants plays a critical role in the etiology of endometriosis [4].

Psychiatry related information on STAR

• The Logic of Argumentation (LA) offers a basis for computerized support of decision-making in the absence of numerical data, and it is being used in a project on carcinogenic risk assessment, StAR [5].
• Measuring the effectiveness of the Star Parenting Program with parents of young children [6].
• PRIMARY OBJECTIVE: To assess the effect of an integrated reality orientation programme (North Star Project) in acute care on the duration of post-traumatic amnesia (PTA) of patients suffering from traumatic brain injury (TBI) [7].
• We studied the response time (RT) and reliability of three neonatal patient-triggered ventilator (PTV) systems: the Draeger Babylog 8000, the Bear Cub enhancement module (CEM), and the Infrasonics Star Sync [8].

High impact information on STAR

• Here we show that the steroidogenic acute regulatory protein (StAR), a mitochondrial protein required for stress responses, reproduction, and sexual differentiation of male fetuses, exerts its activity transiently at the outer mitochondrial membrane rather than at its final resting place in the matrix [9].
• Here we show that DAX-1 binds DNA and acts as a powerful transcriptional repressor of StAR gene expression, leading to a drastic decrease in steroid production [10].
• A rising StAR: an essential role in cholesterol transport [11].
• Liver X receptor opens a new gateway to StAR and to steroid hormones [12].
• 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 [13].

Chemical compound and disease context of STAR

• However, congenital lipoid adrenal hyperplasia is caused by mutations in the steroidogenic acute regulatory protein StAR; it has been thought that P450scc mutations are incompatible with human term gestation, because P450scc is needed for placental biosynthesis of progesterone, which is required to maintain pregnancy [14].
• Mutations in StAR cause congenital lipoid adrenal hyperplasia, a cholesterol storage disorder in which synthesis of all gonadal and adrenocortical steroid hormones is severely impaired, and the cholesterol that is not efficiently moved into the mitochondria accumulates in cytoplasmic lipid droplets [15].
• In this study, we evaluated DAX-1, Ad4BP/SF-1, StAR, and steroidogenic enzyme expressions and their correlations in epithelial ovarian carcinomas to evaluate the possible roles of these factors in regulation of intratumoral steroid metabolism and/or production [16].
• Mutations in StAR are now shown to cause Congenital Lipoid Adrenal Hyperplasia, the last unsolved form of CAH [17].
• Premier Platinum HpSA, as opposed to Hp StAR, cross-reacted with non-pylori Helicobacter spp. in vitro [18].

Biological context of STAR

• We show that the angiotensin II-stimulated transcriptional activation of StAR was dependent upon influx of external calcium and requires protein kinase C activation [19].
• Treatment of the cells with AG490, a selective inhibitor of JAK2, blocked JAK2 activation and StAR reporter gene activity and inhibited steroid production [19].
• Our results demonstrated that LRH-1 plays a critical role in the induction of StAR gene expression [20].
• These findings demonstrate that multiple SF-1 response elements are required for maximal StAR promoter activity and regulation by cAMP [21].
• StAR protein expression is restricted to steroidogenic tissues, and it responds to hormonal stimulation through different second messenger pathways [22].

Anatomical context of STAR

• We examined the effects of oxysterols on the expression of steroidogenic acute regulatory protein (StAR), which increases the delivery of cholesterol to sterol-metabolizing P450s in the mitochondria [1].
• This notion was refuted when it was discovered that sterol regulatory element binding protein-1a is a potent activator of the StAR promoter in CV-1, COS-1, and human granulosa cells [1].
• Human granulosa and theca cells, which express endogenous SF-1, contained more than 5-fold more StAR protein following addition of 27-OHC, whereas StAR mRNA levels remained unchanged [1].
• However, this metabolite inhibited StAR promoter activity in CV-1, COS-1 and CHO cells [1].
• The present study was designed to explore the mechanisms of extracellular calcium (Ca2+) involved in the hCG-stimulated expression of StAR protein and steroidogenesis in a mouse Leydig tumor cell line (mLTC-1) [22].

Associations of STAR with chemical compounds

• We previously reported that StAR mRNA levels and promoter-reporter gene activity in transiently transfected H295R human adrenocortical cells were stimulated by angiotensin II but not by K+ treatment [19].
• Angiotensin II- and K+-stimulated aldosterone production in the adrenocortical glomerulosa cells requires induction of the steroidogenic acute regulatory protein (StAR) [19].
• Moreover, the potent MAPK inhibitors, PD98059 and UO126, augment progesterone production in these cell cultures concomitantly with specific elevation of intracellular steroidogenic acute regulatory protein (StAR) [23].
• Inhibition of protein synthesis by cycloheximide (CHX) drastically diminished the hCG-induced StAR protein content, indicating the requirement for on-going protein synthesis for hCG action [22].
• Interestingly, the calcium ionophore (A23187) clearly increased (P < 0.01) StAR mRNA expression, in additive fashion with hCG [22].
• Multiple lines of evidence show that StAR moves cholesterol from the outer to inner mitochondrial membrane, but acts exclusively on the outer membrane [24].

Physical interactions of STAR

• DNA sequence analysis of the human StAR gene promoter revealed two motifs resembling binding sites for steroidogenic factor 1 (SF-1), a member of the orphan nuclear receptor transcription factor family that controls expression of steroidogenic hydroxylases [25].
• In conclusion, SBP binds StAR protein in cells and enhances the ability of StAR protein to promote syntheses of steroid hormones [26].
• We demonstrate that phosphorylated StAR interacts with voltage-dependent anion channel 1 (VDAC1) on the OMM, which then facilitates processing of the 37-kDa phospho-StAR to the 32-kDa intermediate [27].

Regulatory relationships of STAR

• LRH-1 significantly induced StAR promoter activity in a concentration-dependent manner [20].
• ACTH signaling antagonizes the increase in Dax-1 yet strongly activates StAR transcription [28].
• Antiserum to StAR cross-reacts with N-218 MLN64, indicating the presence of similar epitopes in both proteins [29].
• However, cotransfection with a steroidogenic factor-1 expression plasmid augmented both basal and forskolin-stimulated StAR promoter activity [30].

Other interactions of STAR

• CREM is needed to confer cAMP responsiveness in human StAR protein expression [31].
• 22(R)-hydroxycholesterol (22(R)-OHC), 25-OHC, and 27-OHC each increased steroidogenic factor-1 (SF-1)-mediated StAR gene transactivation by approximately 2-fold in CV-1 cells [1].
• DAX-1 inhibited LRH-1-stimulated StAR promoter activity in a concentration-dependent manner [20].
• The hypothesis that oxysterols act in CV-1 cells to increase StAR promoter activity by reducing nuclear levels of sterol regulatory element binding protein was tested [1].
• The rate-limiting step in the synthesis of steroids in the ovary and the adrenal is the conversion of cholesterol into pregnenolone by cholesterol side-chain cleavage enzyme (P450scc), encoded by the gene CYP11A, after cholesterol is introduced into the mitochondria by the steroidogenic acute regulatory protein (StAR) [32].
• Antagonist analysis also showed that orexin effects on StAR were primarily, but not exclusively, acting through the orexin receptor type 1 [33].

Analytical, diagnostic and therapeutic context of STAR

• Elevation of StAR expression by the MAPK inhibitors involved elevation of StAR mRNA, as demonstrated by RT-PCR in the human cells [23].
• Extracellular Ca2+ (1.5 mmol/liter) enhanced the hCG (50 microg/liter)-induced increases in StAR messenger RNA (mRNA) and protein levels (1.7 +/- 0.3-fold; 4 h), as monitored by quantitative RT-PCR and immunoblotting [22].
• Fluorescence in situ hybridization placed the StAR locus in the region 8p11 [34].
• Third, circular dichroism showed that cholesterol binding induced a change in StAR secondary structure [35].
• The results of pull-down assays and mammalian two-hybrid assays confirmed interaction between N-62 StAR protein and the clone 4 translated product [26].

References