| First Author | Yu RN | Year | 1998 |
| Journal | Mol Endocrinol | Volume | 12 |
| Issue | 7 | Pages | 1010-22 |
| PubMed ID | 9658405 | Mgi Jnum | J:48294 |
| Mgi Id | MGI:1267144 | Doi | 10.1210/mend.12.7.0131 |
| Citation | Yu RN, et al. (1998) The murine Dax-1 promoter is stimulated by SF-1 (steroidogenic factor-1) and inhibited by COUP-TF (chicken ovalbumin upstream promoter-transcription factor) via a composite nuclear receptor-regulatory element. Mol Endocrinol 12(7):1010-22 |
| abstractText | The Dax-1 gene encodes a protein that is structurally related to members of the orphan nuclear receptor superfamily. Dax-1 is coexpressed with another orphan nuclear receptor, steroidogenic factor-1 (SF-1), in the adrenal, gonads, hypothalamus, and pituitary gland. Mutations in Dax-1 cause adrenal hypoplasia congenita, a disorder that is characterized by adrenal insufficiency and hypogonadotropic hypogonadism. These developmental and endocrine abnormalities are similar to those caused by disruption of the murine Ftz-F1 gene (which encodes SF-1), suggesting that these nuclear receptors act along the same developmental cascade. Cloning of the murine Dax-1 gene revealed a candidate SF-1-binding site in the Dax-1 promoter. In transient expression assays in SF-1-deficient JEG-3 cells, SF-1 stimulated expression of the Dax-1 promoter. However, deletion or mutation of the consensus SF-l-binding site did not eliminate SF-1 stimulation. Further analyses revealed the presence of a cryptic SF-1 site that creates an imperfect direct repeat of the SF-1 element. When linked to the minimal thymidine kinase promoter, each of the isolated SF-1 sites was sufficient to mediate transcriptional regulation by SF-1. Mutation of both SF-1 sites eliminated SF-1 binding and stimulation of the Dax-1 promoter. Unexpectedly, mutation of either half of the composite SF-1 sites increased basal activity in JEG-3 cells, suggesting interaction of a repressor protein. Gel shift analyses of the composite response element revealed an additional complex that was not supershifted by SF-1 antibodies. This complex was eliminated by mutation of either half-site, and it was supershifted by antibodies against chicken ovalbumin upstream promoter-transcription factor (COUP-TF). We propose that Dax-1 is stimulated by SF-1, and that SF-l and COUP-TF provide antagonistic pathways that converge upon a common regulatory site. |
