A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor γ

Y. Wang, W. W. Porter, N. Suh, T. Honda, G. W. Gribble, L. M. Leesnitzer, K. D. Plunket, D. J. Mangelsdorf, S. G. Blanchard, T. M. Willson, M. B. Sporn

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

A novel synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), previously reported to have potent differentiating, antiproliferative, and antiinflammatory activities, has been identified as a ligand for the peroxisome proliferator-activated receptor γ (PPARγ). CDDO induces adipocytic differentiation in 3T3-L1 cells, although it is not as potent as the full agonist of PPARγ, rosiglitazone. Binding studies of CDDO to PPARγ using a scintillation proximity assay give a K(i) between 10-8 to 10-7 M. In transactivation assays, CDDO is a partial agonist for PPARγ. The methyl ester of CDDO, CDDO-Me, binds to PPARγ with similar affinity, but is an antagonist. Like other PPARγ ligands, CDDO synergizes with a retinoid X receptor (RXR)-specific ligand to induce 3T3-L1 differentiation, while CDDO-Me is an antagonist in this assay. The partial agonism of CDDO and the antagonism of CDDO-Me reflect the differences in their capacity to recruit or displace cofactors of transcriptional regulation; CDDO and rosiglitazone both release the nuclear receptor corepressor, NCoR, from PPARγ, while CDDO-Me does not. The differences between CDDO and rosiglitazone as either partial or full agonists, respectively, are seen in the weaker ability of CDDO to recruit the coactivator CREB-binding protein, CBP, to PPARγ. Our results establish the triterpenoid CDDO as a member of a new class of PPARγ ligands.

Original languageEnglish (US)
Pages (from-to)1550-1556
Number of pages7
JournalMolecular Endocrinology
Volume14
Issue number10
StatePublished - 2000

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Peroxisome Proliferator-Activated Receptors
rosiglitazone
Ligands
CREB-Binding Protein
3T3-L1 Cells
Retinoid X Receptors
2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
Co-Repressor Proteins
Transcriptional Activation
Anti-Inflammatory Agents
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Wang, Y., Porter, W. W., Suh, N., Honda, T., Gribble, G. W., Leesnitzer, L. M., ... Sporn, M. B. (2000). A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor γ. Molecular Endocrinology, 14(10), 1550-1556.

A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor γ. / Wang, Y.; Porter, W. W.; Suh, N.; Honda, T.; Gribble, G. W.; Leesnitzer, L. M.; Plunket, K. D.; Mangelsdorf, D. J.; Blanchard, S. G.; Willson, T. M.; Sporn, M. B.

In: Molecular Endocrinology, Vol. 14, No. 10, 2000, p. 1550-1556.

Research output: Contribution to journalArticle

Wang, Y, Porter, WW, Suh, N, Honda, T, Gribble, GW, Leesnitzer, LM, Plunket, KD, Mangelsdorf, DJ, Blanchard, SG, Willson, TM & Sporn, MB 2000, 'A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor γ', Molecular Endocrinology, vol. 14, no. 10, pp. 1550-1556.
Wang, Y. ; Porter, W. W. ; Suh, N. ; Honda, T. ; Gribble, G. W. ; Leesnitzer, L. M. ; Plunket, K. D. ; Mangelsdorf, D. J. ; Blanchard, S. G. ; Willson, T. M. ; Sporn, M. B. / A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor γ. In: Molecular Endocrinology. 2000 ; Vol. 14, No. 10. pp. 1550-1556.
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abstract = "A novel synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), previously reported to have potent differentiating, antiproliferative, and antiinflammatory activities, has been identified as a ligand for the peroxisome proliferator-activated receptor γ (PPARγ). CDDO induces adipocytic differentiation in 3T3-L1 cells, although it is not as potent as the full agonist of PPARγ, rosiglitazone. Binding studies of CDDO to PPARγ using a scintillation proximity assay give a K(i) between 10-8 to 10-7 M. In transactivation assays, CDDO is a partial agonist for PPARγ. The methyl ester of CDDO, CDDO-Me, binds to PPARγ with similar affinity, but is an antagonist. Like other PPARγ ligands, CDDO synergizes with a retinoid X receptor (RXR)-specific ligand to induce 3T3-L1 differentiation, while CDDO-Me is an antagonist in this assay. The partial agonism of CDDO and the antagonism of CDDO-Me reflect the differences in their capacity to recruit or displace cofactors of transcriptional regulation; CDDO and rosiglitazone both release the nuclear receptor corepressor, NCoR, from PPARγ, while CDDO-Me does not. The differences between CDDO and rosiglitazone as either partial or full agonists, respectively, are seen in the weaker ability of CDDO to recruit the coactivator CREB-binding protein, CBP, to PPARγ. Our results establish the triterpenoid CDDO as a member of a new class of PPARγ ligands.",
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T1 - A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor γ

AU - Wang, Y.

AU - Porter, W. W.

AU - Suh, N.

AU - Honda, T.

AU - Gribble, G. W.

AU - Leesnitzer, L. M.

AU - Plunket, K. D.

AU - Mangelsdorf, D. J.

AU - Blanchard, S. G.

AU - Willson, T. M.

AU - Sporn, M. B.

PY - 2000

Y1 - 2000

N2 - A novel synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), previously reported to have potent differentiating, antiproliferative, and antiinflammatory activities, has been identified as a ligand for the peroxisome proliferator-activated receptor γ (PPARγ). CDDO induces adipocytic differentiation in 3T3-L1 cells, although it is not as potent as the full agonist of PPARγ, rosiglitazone. Binding studies of CDDO to PPARγ using a scintillation proximity assay give a K(i) between 10-8 to 10-7 M. In transactivation assays, CDDO is a partial agonist for PPARγ. The methyl ester of CDDO, CDDO-Me, binds to PPARγ with similar affinity, but is an antagonist. Like other PPARγ ligands, CDDO synergizes with a retinoid X receptor (RXR)-specific ligand to induce 3T3-L1 differentiation, while CDDO-Me is an antagonist in this assay. The partial agonism of CDDO and the antagonism of CDDO-Me reflect the differences in their capacity to recruit or displace cofactors of transcriptional regulation; CDDO and rosiglitazone both release the nuclear receptor corepressor, NCoR, from PPARγ, while CDDO-Me does not. The differences between CDDO and rosiglitazone as either partial or full agonists, respectively, are seen in the weaker ability of CDDO to recruit the coactivator CREB-binding protein, CBP, to PPARγ. Our results establish the triterpenoid CDDO as a member of a new class of PPARγ ligands.

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