ROS inhibit the expression of testicular steroidogenic enzyme genes via the suppression of Nur77 transactivation.
Steroidogenesis decreases with aging in the testis, whereas the levels of reactive oxygen species (ROS) increase. In addition, ROS have been reported to inhibit testicular steroidogenesis. Here, we investigated the effects of ROS on the transcriptional activity of Nur77, one of the major transcription factors that regulate the expression of steroidogenic enzyme genes. ROS signaling inhibited Nur77 transactivation, which was diminished by either treatment with c-Jun N-terminal kinase (JNK) inhibitor or the expression of a dominant negative form of JNK. This suggests the involvement of JNK signaling, which elevates the expression of c-Jun as well as its phosphorylation in Leydig cells. In transient transfection assays, c-Jun suppressed Nur77 transactivation in a dose-dependent manner. Further studies using c-Jun mutants revealed that the protein level of c-Jun, but not phosphorylation itself, was important for the suppression of Nur77 transactivation. Nur77 directly interacted with c-Jun in vivo, which blocked the DNA binding activity of Nur77. Together, these results suggest that ROS signaling-mediated c-Jun upregulation suppresses the expression of steroidogenic enzyme genes by inhibiting Nur77 transactivation, resulting in the reduction of testicular steroidogenesis. These findings may provide a mechanistic explanation for the age-related decline in testicular steroid hormone production.
Lee
Seung-Yon
SY
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
Gong
Eun-Yeung
EY
Hong
Cheol Yi
CY
Kim
Keon-Hee
KH
Han
Jung-Soo
JS
Ryu
Jae Chun
JC
Chae
Ho Zoon
HZ
Yun
Chul-Ho
CH
Lee
Keesook
K
D000375:Aging / Q000473:pathology / Q000502:physiology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D015971:Gene Expression Regulation, Enzymologic; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D051379:Mice; D009154:Mutation; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013254:Steroid 17-alpha-Hydroxylase / Q000096:biosynthesis / Q000235:genetics; D013256:Steroids / Q000096:biosynthesis*; D015533:Transcriptional Activation / Q000187:drug effects; D000098682:Steroidogenic Acute Regulatory Protein
D000873:Anthracenes; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013256:Steroids; D000098682:Steroidogenic Acute Regulatory Protein; C432165:pyrazolanthrone; D006861:Hydrogen Peroxide; D013254:Steroid 17-alpha-Hydroxylase; D048670:MAP Kinase Kinase 4