Abstract
The development and differentiation of steroidogenic organs are controlled by Ad4BP/SF-1 (adrenal 4 binding protein/steroidogenic factor 1). Besides, lysosomal activity is required for steroidogenesis and also enables adrenocortical cell to survive during stress. However, the role of lysosomal activity on steroidogenic cell growth is as yet unknown. Here, we showed that lysosomal activity maintained Ad4BP/SF-1 protein stability for proper steroidogenic cell growth. Treatment of cells with lysosomal inhibitors reduced steroidogenic cell growth in vitro. Suppression of autophagy did not affect cell growth indicating that autophagy was dispensable for steroidogenic cell growth. When lysosomal activity was inhibited, the protein stability of Ad4BP/SF-1 was reduced leading to reduced S phase entry. Interestingly, treatment of cells with lysosomal inhibitors reduced glycolytic gene expression and supplying the cells with pyruvate alleviated the growth defect. ChIP-sequence/ChIP studies indicated that Ad4BP/SF-1 binds to the upstream region of Ccne1 (cyclin E1) gene during G1/S phase. In addition, treatment of zebrafish embryo with lysosomal inhibitor reduced the levels of the interrenal (adrenal) gland markers. Thus lysosomal activity maintains steroidogenic cell growth via stabilizing Ad4BP/SF-1 protein.
Highlights
Steroid hormones, such as adrenocorticoids, and sex steroids, are mainly produced by the adrenal cortex and gonads; the former steroids maintain energy as well as ionic homeostasis, while the latter steroids are required for sex differentiation and reproductive function[1]
Mouse adrenocortical tumor Y1, progenitor Leydig TM3, and Leydig tumor MA-10 cells were treated with lysosomal inhibitors, chloroquine (CQ), ammonium chloride (NH4Cl) and bafilomycin A1 (Baf), and the growth rates were measured
By counting cell numbers and performing MTT assay, we found that CQ, NH4Cl, and Baf reduced a number of all cell lines tested dose- and time-dependently (Fig. 1A–F and S2A)
Summary
Steroid hormones, such as adrenocorticoids (glucocorticoid and mineralocorticoid), and sex steroids, are mainly produced by the adrenal cortex and gonads; the former steroids maintain energy as well as ionic homeostasis, while the latter steroids are required for sex differentiation and reproductive function[1] All these steroids are synthesized from the common precursor cholesterol. Ad4BP/SF-1 is a tissue type-specific transcription factor belonging to nuclear receptor superfamily[5] It is mainly expressed in the steroidogenic adrenal gland and gonads, and whereby regulate steroidogenic gene expression. Ad4BP/SF-1 binds to the promoter region of Ccne[1] gene regulating its expression during G1/S transition These data reveal the molecular mechanism by which lysosomal activity regulates steroidogenic cell growth via controlling Ad4BP/SF-1 stability
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