Cyclin-Dependent Kinase 5 Regulates Steroidogenic Acute Regulatory Protein and Androgen Production in Mouse Leydig Cells

• Published in: Endocrinology (Philadelphia) Vol. 150; no. 1; pp. 396 - 403
• Main Authors: Lin, Ho, Chen, Mei-Chih, Ku, Chien-Te
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Endocrine Society 01.01.2009
• Subjects: 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; Androgens - biosynthesis; Animals; Biological and medical sciences; Chorionic Gonadotropin - pharmacology; Cyclin-Dependent Kinase 5 - deficiency; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - metabolism; Fundamental and applied biological sciences. Psychology; Kinetics; Leydig Cells - drug effects; Leydig Cells - metabolism; Male; Membrane Transport Proteins - biosynthesis; Mice; Phosphoproteins - genetics; Phosphoproteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - genetics; Testosterone - biosynthesis; Vertebrates: endocrinology; Vertebrata; Mammalia; Androgen; Mouse; Animal; Rodentia; Steroidogenic acute regulatory protein; Sex steroid hormone; Testicle; Male genital system; Cyclin-dependent kinase 5; Leydig cell
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2008-0496

The roles of cyclin-dependent kinase 5 (Cdk5) in central nervous system and neurodegenerative diseases have been intensely investigated in recent decades. Because protein expressions of Cdk5 and its regulator, p35, have been identified in Leydig cells, it is informative to further explore the novel function of Cdk5/p35 in male reproduction. Here we show that Cdk5/p35 protein expression and kinase activity in mouse Leydig cells are regulated by human chorionic gonadotrophin (hCG) in both dose- and time-dependent manners. Blocking of Cdk5 by molecular inhibitors or small interfering RNA resulted in reduction of testosterone production by Leydig cells. cAMP, a second messenger in LH signaling, was identified as a factor in hCG-dependent regulation of Cdk5/p35. Importantly, Cdk5 protein and kinase activity could support accumulation of steroidogenic acute regulatory (StAR) protein, a crucial component of steroidogenesis. We additionally addressed the protein interaction between Cdk5/p35 and StAR. The Cdk5-dependent serine phosphorylation of StAR indicated a possible mechanism by which Cdk5 induced accumulation of StAR protein. In conclusion, Cdk5 modulates hCG-induced androgen production in mouse Leydig cells, possibly through regulation of StAR protein levels. These results indicate that Cdk5 may play an important role in male reproductive endocrinology and is a potential therapeutic target in androgen-related diseases. The physiological function of cyclin-dependent kinase 5 (Cdk5) in mouse Leydig cells is to regulate androgen production through stabilizing the steroiodogenic acute regulatory (StAR) protein.