Document Detail


Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), a negative regulator of luteinizing/chorionic gonadotropin hormone-induced steroidogenesis in Leydig cells: central role of steroidogenic acute regulatory protein (StAR).
MedLine Citation:
PMID:  21719703     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) is a testis-specific gonadotropin-regulated RNA helicase that is present in Leydig cells (LCs) and germ cells and is essential for spermatid development and completion of spermatogenesis. Normal basal levels of testosterone in serum and LCs were observed in GRTH null (GRTH(-/-)) mice. However, testosterone production was enhanced in LCs of GRTH(-/-) mice compared with WT mice by both in vivo and in vitro human chorionic gonadotropin stimulation. LCs of GRTH(-/-) mice had swollen mitochondria with a significantly increased cholesterol content in the inner mitochondrial membrane. Basal protein levels of SREBP2, HMG-CoA reductase, and steroidogenic acute regulatory protein (StAR; a protein that transports cholesterol to the inner mitochondrial membrane) were markedly increased in LCs of GRTH(-/-) mice compared with WT mice. Gonadotropin stimulation caused an increase in StAR mRNA levels and protein expression in GRTH(-/-) mice versus WT mice, with no further increase in SREBP2 and down-regulation of HMG-CoA reductase protein. The half-life of StAR mRNA was significantly increased in GRTH(-/-) mice. Moreover, association of StAR mRNA with GRTH protein was observed in WT mice. Human chorionic gonadotropin increased GRTH gene expression and its associated StAR protein at cytoplasmic sites. Taken together, these findings indicate that, through its negative role in StAR message stability, GRTH regulates cholesterol availability at the mitochondrial level. The finding of an inhibitory action of GRTH associated with gonadotropin-mediated steroidogenesis has provided insights into a novel negative autocrine molecular control mechanism of this helicase in the regulation of steroid production in the male.
Authors:
Masato Fukushima; Joaquin Villar; Chon-Hwa Tsai-Morris; Maria L Dufau
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2011-06-30
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-22     Completed Date:  2011-10-18     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  29932-40     Citation Subset:  IM    
Affiliation:
Section on Molecular Endocrinology, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892-4510, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biological Transport / physiology
Cholesterol / biosynthesis*,  genetics
Chorionic Gonadotropin / pharmacology*
DEAD-box RNA Helicases / biosynthesis*,  genetics
Gene Expression Regulation, Enzymologic / physiology
Humans
Hydroxymethylglutaryl CoA Reductases / biosynthesis,  genetics
Leydig Cells / cytology,  metabolism*
Luteinizing Hormone / pharmacology*
Male
Mice
Mice, Knockout
Mitochondrial Membranes / metabolism*
Phosphoproteins / genetics,  metabolism*
Sterol Regulatory Element Binding Protein 2 / genetics,  metabolism
Chemical
Reg. No./Substance:
0/Chorionic Gonadotropin; 0/Phosphoproteins; 0/SREBF2 protein, human; 0/Srebf2 protein, mouse; 0/Sterol Regulatory Element Binding Protein 2; 0/steroidogenic acute regulatory protein; 57-88-5/Cholesterol; 9002-67-9/Luteinizing Hormone; EC 1.1.1.-/Hydroxymethylglutaryl CoA Reductases; EC 3.6.1.-/DDX25 protein, human; EC 3.6.1.-/DEAD-box RNA Helicases; EC 3.6.1.-/Ddx25 protein, mouse
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