We have been studying the functions of steroid hormones and the regulation of their synthesis. A key enzyme in the steroid synthetic pathway, cytochrome P450scc, is encoded by CYP11A, which is expressed in the adrenal cortex and gonads activated by transcription factor SF-1 (NR5A1). Three different aspects of steroid regulation have been the focus of our investigation.
We have investigated the mechanism that controls SF-1 activation of CYP11A1 transcription in response to cAMP, and found HIPK3 essential via the phosphorylation of JNK and c-Jun. In addition, we find that SF-1 can be modified by ubiquitination, acetylation and sumoylation, which further modulate SF-1 action. The physiological significance of the interplay among these molecules and their nuclear location is under extensive investigation.
We have established mouse models with targeted Cyp11a1 gene disruption. The Cyp11a1 mutant mice are defective in steroid synthesis, forming the basis for the study of steroid functions in sexual development, energy balance, and stress response.
We have studied zebrafish steroidogenic gene functions by knocking down gene expression using antisense morpholino oligos. This results in defects at various stages of development, revealing new functions of steroids in gastrulation, cell migration and tissue differentiation during embryogenesis.