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BioAssay: AID 504790

Summary of the probe development efforts to identify inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1)

Name: Summary of the probe development efforts to identify inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1). ..more
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AID: 504790
Data Source: The Scripps Research Institute Molecular Screening Center (DAX1_INH_SUMMARY)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2011-06-02
Modify Date: 2012-06-21
Target
Related Experiments
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AIDNameTypeComment
504766Luminescence-based primary cell-based high throughput screening assay to identify inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1)Screeningdepositor-specified cross reference: Primary screen (DAX1 inhibitors in singlicate)
588797Luminescence-based cell-based high throughput dose response assay for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1)Confirmatorydepositor-specified cross reference: Dose response (DAX1 inhibitors in triplicate)
588799Counterscreen for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): luminescence-based cell-based high throughput dose response assay to identify compounds that interfere with the UAS/Gal4 system and/or luciferase reporterConfirmatorydepositor-specified cross reference: Dose response counterscreen (UAS/Gal4 system and/or luciferase reporter interference in triplicate)
588821Late stage counterscreen for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): luminescence-based cell-based dose response assay to identify compounds that interfere with the UAS/Gal4 system and/or luciferase reporter.Screeningdepositor-specified cross reference: Late stage counterscreen dose response (compounds that interfere with the UAS/Gal4 system and/or luc
588822Late stage luminescence-based cell-based dose response assay for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1).Screeningdepositor-specified cross reference: Late stage dose response (DAX1 inhibitors in triplicate)
624301Late stage assay provider counterscreen for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): absorbance-based cell-based dose response assay for inhibitors of DAX-1 (CAT activity)Otherdepositor-specified cross reference: Late stage dose response counterscreen (DAX1 inhibitors, CAT activity)
624302Late stage assay provider luminescence-based cell-based dose response assay for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1)Otherdepositor-specified cross reference: Late stage dose response assay (DAX1 inhibitors)
624307Late stage assay provider counterscreen for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): luminescence-based cell-based dose response assay for inhibitors of Star (Steroidogenic acute regulatory protein)Otherdepositor-specified cross reference: Late stage dose response counterscreen (Star inhibitors)
624313Late stage counterscreen for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): absorbance-based cell-based assay to identify inhibitors of the DAX-1 target gene, cytochrome P450, family 11, subfamily A, polypeptide 1 (CYP11A1)Screeningdepositor-specified cross reference: Late stage counterscreen (DAX1 inhibitors)
624314Late stage counterscreen for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1): absorbance-based cell-based assay to identify inhibitors of the DAX-1 target gene, 3B-HSD (3 beta-hydroxysteroid dehydrogenase)Otherdepositor-specified cross reference: Late stage counterscreen (DAX1 inhibitors)
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_INH_SUMMARY

Name: Summary of the probe development efforts to identify inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1).

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).

Summary of Probe Development Effort:

This probe development effort is focused on the identification of identify inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.

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, 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, Gal4, reporter, luciferase, lumi, luminescence, luminescent, chemiluminescence, inhibit, inhibitor, antagonist, adrenal, gonad, steroidogenic, hormone, AHC, stem cell, Ewing, tumor, cancer, primary screen, primary, 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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