Pre-B-Cell Transcription Factor 1 and Steroidogenic Factor 1 Synergistically Regulate Adrenocortical Growth and Steroidogenesis

Abstract

A variety of transcription factors including Wilms tumor gene (Wt-1), steroidogenic factor 1 (Sf-1), dosage-sensitive sex reversal, adrenal hypoplasia congenita on the X-chromosome, Gene 1 (Dax-1), and pre-B-cell transcription factor 1 (Pbx1) have been defined as necessary for regular adrenocortical development. However, the role of Pbx1 for adrenal growth and function in the adult organism together with the molecular relationship between Pbx1 and these other transcription factors have not been characterized. We demonstrate that Pbx haploinsufficiency (Pbx1(+/-)) in mice is accompanied by a significant lower adrenal weight in adult animals compared with wild-type controls. Accordingly, baseline proliferating cell nuclear antigen levels are lower in Pbx1(+/-) mice, and unilateral adrenalectomy results in impaired contralateral compensatory adrenal growth, indicating a lower proliferative potential in the context of Pbx1 haploinsufficiency. In accordance with the key role of IGFs in adrenocortical proliferation and development, real-time RT-PCR demonstrates significant lower expression levels of the IGF-I receptor, and up-regulation of IGF binding protein-2. Functionally, Pbx1(+/-) mice display a blunted corticosterone response after ACTH stimulation coincident with lower adrenal expression of the ACTH receptor (melanocortin 2 receptor, Mc2-r). Mechanistically, in vitro studies reveal that Pbx1 and Sf-1 synergistically stimulates Mc2-r promoter activity. Moreover, Sf-1 directly activates the Pbx1 promoter activity in vitro and in vivo. Taken together, these studies provide evidence for a role of Pbx1 in the maintenance of a functional adrenal cortex mediated by synergistic actions of Pbx1 and Sf-1 in the transcriptional regulation of the critical effector of adrenocortical differentiation, the ACTH receptor.

Bone Morphogenetic Proteins 2 and 5 Are Down-regulated in Adrenocortical Carcinoma and Modulate Adrenal Cell Proliferation and Steroidogenesis

“…Protein extraction and immunoblots were performed as described (18). Phosphorylated Smad1/5/8 (1:500), phosphorylated AKT (pAKT; 1:5,000), total AKT (1:5,000, all from Cell Signaling Technology, Inc.), and h-actin antibody (1:5000; Sigma-Aldrich Corp.) were used as primary antibodies.…”

Gene dosage effects and transcriptional regulation of early mammalian adrenal cortex development

“…Conversely, Pbx1 expression was decreased in Sf-1 haploinsufficient animals. This indicated that Sf-1 could stimulate Pbx1 expression in the adult adrenal [59]. Whether a similar feedforward loop exists in the foetal adrenal is still unknown.…”

Insulin sensitization with a peroxisome proliferator-activated receptor γ agonist prevents adrenocortical lipid infiltration and secretory changes induced by a high-sucrose diet

“…This apparent contradiction can be explained by the fact that sucrose-treated animals display significantly lower Mc2r expression levels in the adrenal cortex (l'Allemand et al 1996, Lichtenauer et al 2007, Waddell et al 2010. The origin and significance of this finding deserve further investigation.…”