SF-1 is a nuclear receptor involved in steroidogenesis, reproduction, development, differentiation and energy homeostasis. SF-1 exerts its functions mainly by activating the expression of its target genes. So far, how SF-1 transcriptional activity is controlled and how SF-1 regulates cell growth are not entirely clear.
To better understand the regulation of SF-1-mediated transcription, SF-1 phosphorylation was systematically analyzed by mass spectrometry and six phosphorylated peptides were found. The effect of phosphorylation on SF-1-mediated transcription was further examined. DNA-binding domain (DBD) phospho-mimicking SF-1 mutants had impaired transcriptional activity and DNA binding ability. Besides, SF-1-48/50/52/54D mutant was less stable, suggesting that SF-1 stability is modulated by DNA-binding domain phosphorylation. In addition, proteolytic activity of proteasomes was required for optimal cAMP-induced, but not basal, CYP11A1 gene expression. Therefore, the roles of phosphorylation and proteasomes in regulating SF-1-mediated transcription were demonstrated.
To study the function of SF-1 in cell growth, SF-1 was depleted in adrenocortical Y1 cells using shRNA. SF-1 depletion caused centrosome amplification, aberrant mitosis and genomic instability, leading to a reduction of cell number. Thus, SF-1 regulates cell growth and prevents centrosome amplification. The centrosome amplification defect was rescued by both wildtype and transcription defective SF-1, suggesting that transcriptional activity is dispensable for SF-1 to maintain centrosome number. Thus, the results uncover a transcription-independent function of SF-1 in the control of centrosome homeostasis and genomic stability.
In summary, studies shown here demonstrate that SF-1 activity is regulated by the negative charge in the DBD and also uncover a new function of SF-1 in maintaining centrosome homeostasis through a transcription-independent manner.

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