Steroidogenic Factor 1, a Goldilocks Transcription Factor from Adrenocortical Organogenesis to Malignancy

Abstract

Steroidogenic factor-1 (SF-1, also termed Ad4BP; NR5A1 in the official nomenclature) is a nuclear receptor transcription factor that plays a crucial role in the regulation of adrenal and gonadal development, function and maintenance. In addition to its classical role in regulating the expression of P450 steroid hydroxylases and other steroidogenic genes, involvement in other key processes such as cell survival/proliferation and cytoskeleton dynamics have also been highlighted for SF-1. SF-1 has a restricted pattern of expression, being expressed along the hypothalamic-pituitary axis and in steroidogenic organs since the time of their establishment. Reduced SF-1 expression affects proper gonadal and adrenal organogenesis and function. On the other hand, SF-1 overexpression is found in adrenocortical carcinoma and represents a prognostic marker for patients' survival. This review is focused on the current knowledge about SF-1 and the crucial importance of its dosage for adrenal gland development and function, from its involvement in adrenal cortex formation to tumorigenesis. Overall, data converge towards SF-1 being a key player in the complex network of transcriptional regulation within the adrenal gland in a dosage-dependent manner.

Keywords: adrenal cortex; adrenocortical carcinoma; gene dosage; nuclear receptors; steroidogenesis; steroidogenic factor 1; transcription factors; tumorigenesis.

Figure 1

Structure of the human SF-1 protein and its target gene categories in tumor adrenocortical cells. The protein domains are shown and corresponding amino acid positions are indicated. SF-1 regulates several key cellular processes. DBD, DNA binding domain; FTZ-F1, FTZ-F1 box; LBD, ligand binding domain.

Figure 2

Timing of SF-1 expression in the mouse embryo along the hypothalamic–pituitary–adrenogonadal axis. SF-1 is expressed in those organs starting from the early stages of development, in particular in the AGP. The developmental stages before birth are indicated in days post-conception.

Figure 3

Adrenal phenotypes associated with an altered SF-1 dosage in mice and humans.

Figure 4

A model for the role of SF-1 in the control of adrenocortical cell differentiation in the human fetal adrenal. A gradient of SF-1 expression exists, with higher levels in the FZ compared with the DZ. Additionally, the DAX-1 repressor is expressed at higher levels and shows more pronounced nuclear localization in the DZ compared with the FZ. This leads to presumed higher transcriptional activity of SF-1 in the FZ compared with the DZ and differential regulation of the expression of its dosage-dependent target genes. C, adrenal capsule; DZ, definitive zone; TZ, transitional zone; FZ, fetal zone.