Disease relevance of STAR

• A point mutant of StAR (A218V) that causes lipoid congenital adrenal hyperplasia was incorporated into the His-tag protein [1].
• To determine whether cytosolic factors are required for StAR action, we developed an assay system using washed mitochondria isolated from bovine corpora lutea and purified recombinant His-tag StAR proteins expressed in Escherichia coli [1].

High impact information on STAR

• Angiotensin II (Ang II) and adrenocorticotropic hormone stimulate aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex through induction of the expression of the steroidogenic acute regulatory (StAR) protein, which promotes intramitochondrial cholesterol transfer [2].
• We therefore examined the effect of TGF-beta1 on the expression of StAR, a mitochondrial protein implicated in intramitochondrial cholesterol transport [3].
• Using metabolically labeled COS-1 cells transfected with wild-type or His-tag StAR constructs, we confirmed that wild-type StAR preprotein was imported and processed by mitochondria, whereas His-tag StAR remained largely cytosolic and unprocessed [1].
• There was no evidence at the light or electron microscope levels for selective localization of His-tag StAR protein to mitochondrial membranes [1].
• His-tag StAR proteins stimulated pregnenolone synthesis to the same extent as wild-type StAR when expressed in COS-1 cells transfected with the cholesterol side-chain cleavage system [1].

Biological context of STAR

• The bovine StAR gene is transcribed as 3kb and 1.8kb transcripts, which differ in their sites of 3' polyadenylation [4].
• Within the protein coding region of the bovine StAR gene, there is a marked 124 base homology to the 5' non-coding region of another luteal transcript, TIMP-1, suggesting a possible common regulatory function for this sequence [4].
• These results demonstrate that Ca2+ exerts a transcriptional control on StAR protein expression and that ANP appears to elicit its inhibitory effect on aldosterone biosynthesis by acting as a negative physiological regulator of StAR gene expression [5].
• A potent MEK inhibitor PD98059 eliminated ERK phosphorylation and augmented progesterone production concomitantly with the elevation of intracellular steroidogenic acute regulatory protein mRNA in LH/forskolin-stimulated theca cells [6].
• In both cell systems, detectable upregulation of StAR gene transcription occurred within 1-2 h, reaching maxima at 4 h (theca cells) or 6 h (adrenocortical cells). mRNA levels returned rapidly to baseline, by 12 h or 24 h, respectively [7].

Anatomical context of STAR

• In contrast, His-tag StAR was not imported and protein associated with mitochondria was sensitive to trypsin [1].
• Our observations conclusively document that StAR acts on the outside of mitochondria, independent of mitochondrial import, and in the absence of cytosol [1].
• Atrial natriuretic peptide inhibits calcium-induced steroidogenic acute regulatory protein gene transcription in adrenal glomerulosa cells [5].
• Induction of Ad4BP/SF-1, steroidogenic acute regulatory protein, and cytochrome P450scc enzyme system expression in newly established human granulosa cell lines [8].
• However, granulosa or luteinized granulosa of some advanced or late atretic follicles expressed StAR mRNA [9].

Associations of STAR with chemical compounds

• Recombinant His-tag StAR stimulated pregnenolone production in a dose- and time-dependent manner, functioning at nanomolar concentrations [1].
• StAR is synthesized in the cytoplasm and is subsequently imported by mitochondria and processed to a mature form by cleavage of the NH2-terminal mitochondrial targeting sequence [1].
• The octapeptide hormone, angiotensin II (AngII) and ACTH stimulate mineralocorticoid biosynthesis in the zona glomerulosa of the adrenal cortex in part by promoting the transcription of the gene coding for the steroidogenic acute regulatory (StAR) protein [10].
• Levels of mRNA encoding steroidogenic acute regulatory protein, P450scc, and 3beta-hydroxy- steroid dehydrogenase were also reduced but to a much lesser extent [11].
• In the present study, we have assessed the kinetics of both StAR gene transcription and protein biosynthesis in primary cell cultures of bovine adrenocortical and ovarian theca cells, under conditions of acute stimulation by corticotrophin (ACTH) and luteinizing hormone (LH), respectively [7].

Physical interactions of STAR

• PC-TP is structurally homologous to the lipid-binding domain of the steroidogenic acute regulatory protein (Nat. Struct. Biol. 7 (2000) 408) [12].

Regulatory relationships of STAR

• The next objective was to determine if oxytocin regulates LH-stimulated steroidogenesis by modulating the levels of mRNA for steroidogenic enzymes and/or Steroidogenic Acute Regulatory protein (StAR) [13].

Other interactions of STAR

• Under conditions inducing luteal differentiation of theca cells, CYP11A1 and STAR (Steroidogenic acute regulatory protein) were up-regulated by the action of luteinizing hormone (LH), whereas the differentiation-specific up-regulation of INSL3 was suppressed by LH in luteinizing theca cells [14].
• Transforming growth factor beta1 decreases cholesterol supply to mitochondria via repression of steroidogenic acute regulatory protein expression [3].
• Furthermore, modulation of ERK phosphorylation involves control of thecal steroidogenesis via modulation of the expression of steroidogenic acute regulatory protein and P450c17 [6].
• Ovarian follicular steroidogenic acute regulatory protein, low-density lipoprotein receptor, and cytochrome P450 side-chain cleavage messenger ribonucleic acids in cattle undergoing superovulation [15].

Analytical, diagnostic and therapeutic context of STAR

• Molecular cloning and in vivo expression of the bovine steroidogenic acute regulatory protein [4].
• Specific StAR protein levels were assessed by western blotting using a novel antibody raised against a bovine StAR peptide, and showed a similar fast upregulation, albeit delayed by 1-2 h compared with the mRNA [7].
• In ovaries of abattoir origin, StAR mRNA was detected in all follicles and was present in the theca but not the granulosa cell layer, as shown by Northern blotting [15].
• Expression of StAR mRNA was localized by in situ hybridization and quantified by image analysis [9].
• StAR mRNA was detectable by RT-PCR, did not change with duration of culture and was not correlated with progesterone secretion [16].

References