c-Jun Is Involved in cAMP-stimulated Expression of CYP11A1

• Main Authors: Hua-Jung Li, 李華容
• Other Authors: Bon-Chu Chung
• Format: Others
• Language: en_US
• Published: 2003
• Online Access: http://ndltd.ncl.edu.tw/handle/00083445824859236948

碩士 === 國立陽明大學 === 生物化學研究所 === 91 === Steroids are important for glucose metabolism, salt balance, and brain and sexual development. All steroid hormones are derived from cholesterol. The first and rate-limiting step in steroidogenesis is catalyzed by cytochrome P450scc (CYP11A1). Therefore, CYP11A1 is very important in regulation of steroidogenesis. The expression of CYP11A1 in adrenal is regulated by adrenocorticotropin and its receptor using cAMP as the intracellular signals. However, the downstream mechanism is unclear because the time course of CREB activation, a typical downstream factor in cAMP-PKA signaling pathway, is not correlated with the time course of CYP11A1 activation. We have analyzed the elements on the promoter of CYP11A1 for response to cAMP. We found there is a cAMP-responsive region at ~1.6 kb from transcriptional start site, which contains an SF-1 binding site (-1616/-1609) in the middle of two TRE-like element. On the other hand, c-Jun interacts directly with SF-1, which is proved by GST-pull down and co-immunoprecipitation, and synergistically enhances SF-1-mediated transcription. Expression of N-terminal deleted c-Jun (a.a. 149-331) or unphosphorylable c-Jun (Ala-c-Jun) impairs the cAMP-stimulated expression of endogenous CYP11A1 in Y1 adrenocortical cell. Expression of active c-Jun (Asp-c-Jun) enhances expression of endogenous CYP11A1 in Y1 adrenocortical cell. Furthermore, JNK inhibitor (SP600125) represses the CYP11A1 gene expression to 60% under cAMP stimulation. These results indicate that c-Jun N-terminal phosphorylation is important for the cAMP-stimulated expression of CYP11A1 and JNK is involved in the cAMP signaling pathway. My finding implies c-Jun may be a novel downstream factor in cAMP-PKA signaling pathway.