Phosphorylation and function of the hamster adrenal steroidogenic acute regulatory protein (StAR)

Fleury, Alain; Mathieu, Axel; Ducharme, Lyne; Hales, Dale B.; Lehoux, Jean‐Guy

doi:10.1016/j.jsbmb.2004.04.010

Cited by 52 publications

(40 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Phosphorylation of STAR at residue S194 has been shown to be required for its maximal steroidogenic activity (65,66). Thus, it is possible that AMPK activation impairs steroidogenesis by reducing STAR protein activity via modulation of its phosphorylation status.…”

Section: Discussionmentioning

confidence: 99%

A Cell-Autonomous Molecular Cascade Initiated by AMP-Activated Protein Kinase Represses Steroidogenesis

Abdou

Bergeron

Tremblay

2014

Molecular and Cellular Biology

View full text Add to dashboard Cite

bSteroid hormones regulate essential physiological processes, and inadequate levels are associated with various pathological conditions. In testosterone-producing Leydig cells, steroidogenesis is strongly stimulated by luteinizing hormone (LH) via its receptor leading to increased cyclic AMP (cAMP) production and expression of the steroidogenic acute regulatory (STAR) protein, which is essential for the initiation of steroidogenesis. Steroidogenesis then passively decreases with the degradation of cAMP into AMP by phosphodiesterases. In this study, we show that AMP-activated protein kinase (AMPK) is activated following cAMP-to-AMP breakdown in MA-10 and MLTC-1 Leydig cells. Activated AMPK then actively inhibits cAMP-induced steroidogenesis by repressing the expression of key regulators of steroidogenesis, including Star and Nr4a1. Similar results were obtained in Y-1 adrenal cells and in the constitutively steroidogenic R2C cells. We have also determined that maximum AMPK activation following stimulation of steroidogenesis in MA-10 Leydig cells occurs when steroid hormone production has reached a plateau. Our data identify AMPK as a molecular rheostat that actively represses steroid hormone biosynthesis to preserve cellular energy homeostasis and prevent excess steroid production.

show abstract

Section: Discussionmentioning

confidence: 99%

A Cell-Autonomous Molecular Cascade Initiated by AMP-Activated Protein Kinase Represses Steroidogenesis

Abdou

Bergeron

Tremblay

2014

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…In the great majority of the 183 cases mentioned above, the water-mediated hydrogen bond network between cho- lesterol and the receptor is predicted to involve a single water molecule, which would interact predominantly with the carbonyl group of Leu199 only (133 cases) but also with the side chain of Arg188 (50 cases). Interestingly, mutations of the side chains of Arg188 and glutamate 169 (Glu169), which form an ion pair, have indeed been shown to lead to a loss of function (13,74), although it is not clear whether this reflects an actual involvement in ligand binding (20,74) or simply a structural role during folding of the polypeptide chain (13,34,75).…”

Section: Structural Models Of Cholesterol-start Domain Complexesmentioning

confidence: 99%

Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol

Murcia

Faraldo‐Gómez

Maxfield

et al. 2006

Journal of Lipid Research

106

121

View full text Add to dashboard Cite

Steroidogenic acute regulatory protein-related lipid transfer (StART) domains are ubiquitously involved in intracellular lipid transport and metabolism and other cell-signaling events. In this work, we use a flexible docking algorithm, comparative modeling, and molecular dynamics (MD) simulations to generate plausible three-dimensional atomic models of the StART domains of human metastatic lymph node 64 (MLN64) and steroidogenic acute regulatory protein (StAR) proteins in complex with cholesterol. Our results show that cholesterol can adopt a similar conformation in the binding cavity in both cases and that the main contribution to the protein-ligand interaction energy derives from hydrophobic contacts. However, hydrogen-bonding and water-mediated interactions appear to be important in the fine-tuning of the binding affinity and the position of the ligand. To gain insights into the mechanism of binding, we carried out steered MD simulations in which cholesterol was gradually extracted from within the StAR model. These simulations indicate that a transient opening of loop 61 may be sufficient for uptake and release, and they also reveal a pathway of intermediate states involving residues known to be crucial for StAR activity. Based on these observations, we suggest specific mutagenesis targets for binding studies of cholesterol and its derivatives that could improve our understanding of the structural determinants for ligand binding by sterol carrier proteins.-Murcia, M., J. D. Faráldo-Gómez, F. R. Maxfield, and B. Roux. Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol.

show abstract

“…30 In addition, PKA is considered to be an important positive regulator of StAR activity by posttranslational phosphorylation. 32 We, therefore, investigated the effect of ACM on the cAMP/PKA/CREB signaling cascade. ACM-mediated aldosterone production was not accompanied by cAMP production, and inhibition of PKA failed to reduce ACM-induced aldosterone synthesis.…”

Section: Adipokines Regulate Star In Adrenocortical Cells Aw Krug Et Almentioning

confidence: 99%

Human adipocytes induce an ERK1/2 MAP kinases-mediated upregulation of steroidogenic acute regulatory protein (StAR) and an angiotensin II — sensitization in human adrenocortical cells

et al. 2007

View full text Add to dashboard Cite

Objectives: Hypertension is a major complication of overweight with frequently elevated aldosterone levels in obese patients. Our previous work suggests a direct stimulation of adrenal aldosterone secretion by adipocytes. Owing to aldosterone's important role in maintaining blood pressure homeostasis, its regulation in obesity is of major importance. One objective was to determine the signaling mechanisms involved in adipocyte-induced aldosterone secretion. In addition to a direct stimulation, a sensitization toward angiotensin II (AngII) might be involved. The second objective was to determine a possible adipokinesinduced sensitization of human adrenocortical cells to AngII. Design: Human subcutaneous adipocytes and adrenocortical cells, and the adrenocortical cell line NCI-H295R were used. Adrenocortical cells were screened for signal transduction protein expression and phosphorylation. Subsequently, steroidogenic acute regulatory protein (StAR), cAMP response element-binding protein (CREB), cAMP and phosphorylated extracellular regulated kinase were analyzed by Western blot, enzyme-linked immunosorbent assay, quantitative PCR, reporter gene assay and confocal microscopy to investigate their role in adipocyte-mediated aldosterone secretion. Results: AngII-mediated aldosterone secretion was largely increased by preincubating H295R cells with adipocyte secretory products. StAR mRNA and StAR protein were upregulated in a time-dependent way. This steroidogenic effect was independent of the cAMP-protein kinase A (PKA) pathway as cellular cAMP was unaltered and inhibition of PKA by H89 failed to reduce aldosterone secretion. However, CREB reporter gene activity was moderately elevated. Upregulation of StAR was accompanied by ERK1/2 MAP kinase activation and nuclear translocation of the kinases. Inhibition of MAP kinase by UO126 abolished adipokine-stimulated aldosterone secretion from primary human adrenocortical and H295R cells, and inhibited StAR gene activity. Adipokines stimulated steroidogenesis also in primary human adrenocortical cells, supporting a role in human physiology and/or pathology. Conclusions: Adipokines induce aldosterone secretion from human adrenocortical cells and sensitization of the cells to stimulation by AngII, possibly mediated via ERK1/2-dependent upregulation of StAR activity. This stimulation of aldosterone secretion could be one link between overweight and inappropriately elevated aldosterone levels.

show abstract

Phosphorylation and function of the hamster adrenal steroidogenic acute regulatory protein (StAR)

Cited by 52 publications

References 49 publications

A Cell-Autonomous Molecular Cascade Initiated by AMP-Activated Protein Kinase Represses Steroidogenesis

A Cell-Autonomous Molecular Cascade Initiated by AMP-Activated Protein Kinase Represses Steroidogenesis

Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol

Human adipocytes induce an ERK1/2 MAP kinases-mediated upregulation of steroidogenic acute regulatory protein (StAR) and an angiotensin II — sensitization in human adrenocortical cells

Contact Info

Product

Resources

About