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BioAssay: AID 652012

Summary of the probe development effort to identify inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): repression of SF-1 (NR5A1) activated StAR promoter by full-length DAX-1

Name: Summary of the probe development effort to identify inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): repression of SF-1 (NR5A1) activated StAR promoter by full-length DAX-1. ..more
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AID: 652012
Data Source: The Scripps Research Institute Molecular Screening Center (DAX1-FULL_INH_SUMMARY)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2013-02-04
Modify Date: 2013-03-20
Target
Depositor Specified Assays
AIDNameTypeComment
652010Luminescence-based cell-based primary high throughput screening assay for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): repression of SF-1 (NR5A1) activated StAR promoter by full-length DAX-1screeningPrimary screen (full-length DAX1 inhibitors in singlicate)
652134Luminescence-based cell-based primary high throughput confirmation assay for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): repression of SF-1 (NR5A1) activated StAR promoter by full-length DAX-1screeningConfirmation screen (full-length DAX1 inhibitors in triplicate)
652136Counterscreen for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): Luminescence-based cell-based high throughput assay for nonselective inhibitors/assay artifacts using AP2 mutant SF-1 (NR5A1) Transactivation AssayscreeningCounterscreen (artifacts in triplicate)
687017Luminescence-based cell-based high throughput dose response assay for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): repression of SF-1 (NR5A1) activated StAR promoter by full-length DAX-1confirmatory
687018Counterscreen for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): Luminescence-based cell-based high throughput dose response assay for nonselective inhibitors/assay artifacts using AP2 mutant SF-1 (NR5A1) Transactivation Assayconfirmatory
Description:
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Enzo Lalli, CNRS
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: R03 DA030558-01
Grant Proposal PI: Enzo Lalli, CNRS
External Assay ID: DAX1-FULL_INH_SUMMARY

Name: Summary of the probe development effort to identify inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): repression of SF-1 (NR5A1) activated StAR promoter by full-length DAX-1.

Description:

Nuclear receptors are a family of small molecule and hormone-regulated transcription factors that share conserved DNA-binding (DBD) and ligand-binding domains (LBD) (1-3). Of interest, DAX-1 (NR0B1; nuclear receptor subfamily 0, group B, member 1; dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome gene 1) is an orphan nuclear receptor shown to act as a robust transcriptional repressor, inhibiting genes involved in steroidogenesis through interaction with corepressors and regulating the pluripotency of stem cells (4-8). The human DAX-1 gene encodes a protein whose C terminus is similar to the LBD of nuclear hormone receptors, while its N terminus is composed of three cysteine-rich 70 amino acids with little similarity to known proteins (4, 7). Mutations in DAX-1 have been shown to cause the X-linked form of adrenal hypoplasia congenita (AHC), associated with hypogonadotropic hypogonadism (HHG). AHC-HHG-associated mutations share an altered DAX-1 C-terminal domain (5, 9), resulting in loss of transcriptional repression activity (5, 7, 9), which suggests that impairment of the DAX-1 transcriptional activity is directly linked to AHC-HHG pathogenesis. In addition, DAX-1 is highly expressed in pediatric Ewing tumors (10). As a result, the identification of selective inhibitors of DAX-1 will serve as useful tools to elucidate its roles of in steroidogenesis, tumorigenesis, and maintenance of stem cell pluripotency (8).

References:

1. Evans RM. The nuclear receptor superfamily: a rosetta stone for physiology. Mol Endocrinol 19: 1429-1438, 2005.
2. Kliewer SA, Lehmann JM, and Willson TM. Orphan nuclear receptors: shifting endocrinology into reverse. Science 284: 757-760, 1999.
3. Li Y, Lambert MH, and Xu HE. Activation of nuclear receptors: a perspective from structural genomics. Structure 11: 741-746, 2003.
4. Lalli, E., M. H. Melner, D. M. Stocco, and P. Sassone-Corsi. DAX-1 blocks steroid production at multiple levels. Endocrinology 139: 4237-4243, 1998.
5. Ito, M., R. Yu, and J. L. Jameson. DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenita. Mol. Cell. Biol. 17: 1476-1483, 1997.
6. Zazopoulos, E., E. Lalli, D. M. Stocco, and P. Sassone-Corsi. DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis. Nature 390: 311-315, 1997.
7. Lalli, E., B. Bardoni, E. Zazopoulos, J.-M. Wurtz, T. M. Strom, D. Moras, and P. Sassone-Corsi. A transcriptional silencing domain in DAX-1 whose mutation causes adrenal hypoplasia congenita. Mol. Endocrinol. 11: 1950-1960, 1997.
8. Lalli E, Alonso J. Targeting DAX-1 in embryonic stem cells and cancer. Expert Opin Ther Targets 14: 169-77, 2010.
9. Zanaria, E., F. Muscatelli, B. Bardoni, T. M. Strom, S. Guioli, W. Guo, E. Lalli, C. Moser, A. P. Walker, E. R. B. McCabe, T. Meitinger, A. P. Monaco, P. Sassone-Corsi, and G. Camerino. 1994. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372:635-641.
10. Mendiola M, Carrillo J, Garcia E, Lalli E, Hernandez T, de Alava E, Tirode F, Delattre O, Garcia-Miguel P, Lopez-Barea F, Pestana A, Alonso J. The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. Int J Cancer. 2006 Mar 15;118(6):1381-9.

Keywords:

Summary, Summary AID, transactivation, co-transfection, reporter, luc, lumi, luminescence, luciferase, promoter, StAR, SF-1, NR5A1, DAX-1, Dax, Dax1, NR0B1, dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1, orphan, nuclear, nuclear receptor, NR, X chromosome, inhibit, inhibitor, antagonist, adrenal, gonad, steroidogenic, hormone, AHC, stem cell, Ewing, tumor, cancer, primary screen, singlicate, HTS, high throughput screen, 1536, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Additional Information
Grant Number: R03 DA030558-01

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