The differential regulation of steroidogenic acute regulatory protein-mediated steroidogenesis by type I and type II PKA in MA-10 cells

Both retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mediate the action of retinoids that play important roles in reproductive development and function, as well as steroidogenesis. Regulation of steroid biosynthesis is principally mediated by the steroidogenic acute regulatory protein (StAR); however, the modes of action of retinoids in the regulation of steroidogenesis remain obscure. In this study we demonstrate that all-trans retinoic acid (atRA) enhances StAR expression, but not its phosphorylation (P-StAR), and progesterone production in MA-10 mouse Leydig cells. Activation of the protein kinase A (PKA) cascade, by dibutyrl-cAMP or type I/II PKA analogs, markedly increased retinoid-responsive StAR, P-StAR, and steroid levels. Targeted silencing of endogenous RARα and RXRα, with small interfering RNAs, resulted in decreases in 9-cis RA-stimulated StAR and progesterone levels. Truncation of and mutational alterations in the 5′-flanking region of the StAR gene demonstrated the importance of the −254/−1-bp region in retinoid responsiveness. An oligonucleotide probe encompassing an RXR/liver X receptor recognition motif, located within the −254/−1-bp region, specifically bound MA-10 nuclear proteins and in vitro transcribed/translated RXRα and RARα in EMSAs. Transcription of the StAR gene in response to atRA and dibutyrl-cAMP was influenced by several factors, its up-regulation being dependent on phosphorylation of cAMP response-element binding protein (CREB). Chromatin immunoprecipitation studies revealed the association of phosphorylation of CREB, CREB binding protein, RXRα, and RARα to the StAR promoter. Further studies elucidated that hormone-sensitive lipase plays an important role in atRA-mediated regulation of the steroidogenic response that involves liver X receptor signaling. These findings delineate the molecular events by which retinoids influence cAMP/PKA signaling and provide additional and novel insight into the regulation of StAR expression and steroidogenesis in mouse Leydig cells.

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Novel Action of Activin and Bone Morphogenetic Protein in Regulating Aldosterone Production by Human Adrenocortical Cells

Endocrinology ◽

10.1210/en.2003-0968 ◽

2004 ◽

Vol 145 (2) ◽

pp. 639-649 ◽

Cited By ~ 43

Author(s):

Jiro Suzuki ◽

Fumio Otsuka ◽

Kenichi Inagaki ◽

Masaya Takeda ◽

Toshio Ogura ◽

...

Keyword(s):

Bone Morphogenetic Protein ◽

Regulatory Protein ◽

Mapk Signaling ◽

Steroidogenic Acute Regulatory Protein ◽

Mrna Levels ◽

Type Ii ◽

Ang Ii ◽

Morphogenetic Protein ◽

Aldosterone Production ◽

Steroidogenic Acute Regulatory

Abstract We have uncovered a functional bone morphogenetic protein (BMP) and activin system complete with ligands (BMP-6 and activin βA/βB), receptors (activin receptor-like kinase receptors 2, 3, and 4; activin type-II receptor; and BMP type-II receptor), and the binding protein follistatin in the human adrenocortical cell line H295R. Administration of activin and BMP-6 to cultures of H295R cells caused concentration-responsive increases in aldosterone production. The mRNA levels of steroidogenic acute regulatory protein or P450 steroid side-chain cleavage enzyme, the rate-limiting steps of adrenocortical steroidogenesis, were enhanced by activin and BMP-6. Activin and BMP-6 also activated the transcription of steroidogenic acute regulatory protein as well as the late-step steriodogenic enzyme CYP11B2. Activin enhanced ACTH-, forskolin-, or dibutyryl-cAMP- but not angiotensin II (Ang II)-induced aldosterone production, whereas BMP-6 specifically augmented Ang II-induced aldosterone production. Activin and ACTH but not BMP-6 increased cAMP production. Follistatin, which inhibits activin actions by binding, suppressed basal and ACTH-induced aldosterone secretion but failed to affect the Ang II-induced aldosterone level. Furthermore, MAPK signaling appeared to be involved in aldosterone production induced by Ang II and BMP-6 because an inhibitor of MAPK activation, U0126, reduced the level of aldosterone synthesis stimulated by Ang II and BMP-6 but not activin. In addition, Ang II reduced the expression levels of BMP-6 but increased that of activin βB, whereas ACTH had no effect on these levels. Collectively, the present data suggest that activin acts to regulate adrenal aldosterone synthesis predominantly by modulating the ACTH-cAMP-protein kinase A signaling cascade, whereas BMP-6 works primarily by modulating the Ang II-MAPK cascade in human adrenal cortex in an autocrine/paracrine fashion.

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Higher Levels of Steroidogenic Acute Regulatory Protein and Type I 3β-Hydroxysteroid Dehydrogenase in the Scalp of Men with Androgenetic Alopecia

Journal of Investigative Dermatology ◽

10.1038/sj.jid.5700442 ◽

2006 ◽

Vol 126 (10) ◽

pp. 2332-2335 ◽

Cited By ~ 19

Author(s):

WenChieh Chen ◽

Shaw-Jenq Tsai ◽

Chen-Yu Liao ◽

Ren-Yeu Tsai ◽

Yi-Ju Chen ◽

...

Keyword(s):

Regulatory Protein ◽

Hydroxysteroid Dehydrogenase ◽

Androgenetic Alopecia ◽

Steroidogenic Acute Regulatory Protein ◽

Type I ◽

Steroidogenic Acute Regulatory

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Mitochondrial A-Kinase Anchoring Protein 121 Binds Type II Protein Kinase A and Enhances Steroidogenic Acute Regulatory Protein-Mediated Steroidogenesis in MA-10 Mouse Leydig Tumor Cells1

Biology of Reproduction ◽

10.1095/biolreprod.107.064238 ◽

2008 ◽

Vol 78 (2) ◽

pp. 267-277 ◽

Cited By ~ 43

Author(s):

Matthew T. Dyson ◽

Jeffrey K. Jones ◽

Mariusz P. Kowalewski ◽

Pulak R. Manna ◽

Manuela Alonso ◽

...

Keyword(s):

Protein Kinase ◽

Protein Kinase A ◽

Regulatory Protein ◽

Steroidogenic Acute Regulatory Protein ◽

Type Ii ◽

Anchoring Protein ◽

Steroidogenic Acute Regulatory ◽

Kinase A

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Von Hermaphroditos der griechischen Mythologie bis zu DSD der Moderne

Praxis ◽

10.1024/1661-8157.98.1.31 ◽

2008 ◽

Vol 98 (1) ◽

pp. 31-34

Author(s):

Oestmann ◽

Mullis ◽

Stanga

Keyword(s):

Regulatory Protein ◽

Steroidogenic Acute Regulatory Protein ◽

Sich Eine ◽

Fand Sich ◽

Steroidogenic Acute Regulatory

Wir berichten über eine heute 34-jährige Frau, die im Alter von 6 Monaten wegen rezidivierendem Erbrechen hospitalisiert werden musste. Als Ursache fand sich eine Nebenniereninsuffizienz mit Verminderung sämtlicher Hormone der Steroidhormonbiosynthese. Die weiteren Abklärungen ergaben bei dem phänotypisch weiblichen Säugling eine lipoide kongenitale adrenale Hyperplasie mit 46,XY DSD. 24 Jahre später konnte in der DNS-Sequenzanalyse ein homozygoter, in der Schweiz vorkommender Basenaustausch des steroidogenic acute regulatory protein-Gens gefunden werden, welcher zu einem Aminosäurenaustausch Leucin 260 Prolin (L260P) führt.

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