| Summary: | 博士 === 國立陽明大學 === 生化暨分子生物研究所 === 95 === Abstract
Steroids are synthesized in adrenals and gonads under the control of pituitary peptides. These peptides bind to cell surface receptors to activate the cAMP signaling pathway leading to an increase of steroidogenic gene expression. Exactly how cAMP is linked to steroidogenic gene expression is not clear, except for the knowledge that transcription factor SF-1 plays a key role for steroidogenic gene transcription. Investigating factors participating in SF-1 action, I found that c-Jun and Homeodomain-Interacting Protein Kinase 3 (HIPK3) were required for basal and cAMP-stimulated expression of one major steroidogenic gene, CYP11A1. HIPK3 enhanced SF-1 activity, but c-Jun was required for the interaction of HIPK3 with SF-1. Furthermore, after cAMP stimulation, c-Jun and Jun N-Terminal Kinase (JNK) were phosphorylated through HIPK3. These phosphorylations were important for SF-1 activity and CYP11A1 expression. Thus I have defined HIPK3-mediated JNK activity and c-Jun phosphorylation as an important event that increases SF-1 activity for CYP11A1 transcription in response to cAMP. This finding has linked two common factors, HIPK3 and c-Jun, to the cAMP signaling pathway leading to increased steroidogenic gene expression.
In addition to HIPK3 and c-Jun, Retinoblastoma protein (pRB), the cell cycle regulator, was also defined as an interacting protein of SF-1. Pull down assay and co-immunoprecipitation confirmed that pRB directly binds to SF-1. However, pRB represses transcriptional activity of SF-1 in CYP11A1, StAR and Dax-1 promoters which is different from HIPK3 and c-Jun. The regulation of pRB and SF-1 is probably involved in controlling cell growth, embryo development or tumor progression and the authentic physiological function should be further studied.
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