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

被引:162
作者
Wang, YP
Porter, WW
Suh, NJ
Honda, T
Gribble, GW
Leesnitzer, LM
Plunket, KD
Mangelsdorf, DJ
Blanchard, SG
Willson, TM
Sporn, MB [1 ]
机构
[1] Dartmouth Med Sch, Dept Pharmacol, Hanover, NH 03755 USA
[2] Dartmouth Med Sch, Dept Chem, Hanover, NH 03755 USA
[3] Dartmouth Coll, Hanover, NH 03755 USA
[4] Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dallas, TX 75390 USA
[5] Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75390 USA
[6] Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA
[7] Glaxo Wellcome Inc, Res & Dev, Dept Mol Biochem, Res Triangle Pk, NC 27709 USA
[8] Glaxo Wellcome Inc, Res & Dev, Dept Mol Endocrinol, Res Triangle Pk, NC 27709 USA
[9] Glaxo Wellcome Inc, Res & Dev, Dept Med Chem, Res Triangle Pk, NC 27709 USA
关键词
D O I
10.1210/me.14.10.1550
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
A novel synthetic triterpenoid, 2-cyano-3,12-dioxooieana-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 gamma (PPAR gamma). CDDO induces adipocytic differentiation in 3T3-L1 cells, although it is not as potent as the full agonist of PPAR gamma, rosiglitazone. Binding studies of CDDO to PPAR gamma 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 PPAR gamma. The methyl ester of CDDO, CDDO-Me, binds to PPAR gamma with similar affinity, but is an antagonist. Like other PPAR gamma 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 PPAR gamma, 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 PPAR gamma. Our results establish the triterpenoid CDDO as a member of a new class of PPAR gamma ligands.
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收藏
页码:1550 / 1556
页数:7
相关论文
共 35 条
  • [21] A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation
    Oberfield, JL
    Collins, JL
    Holmes, CP
    Goreham, DM
    Cooper, JP
    Cobb, JE
    Lenhard, JM
    Hull-Ryde, EA
    Mohr, CP
    Blanchard, SG
    Parks, DJ
    Moore, LB
    Lehmann, JM
    Plunket, K
    Miller, AB
    Milburn, MV
    Kliewer, SA
    Willson, TM
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (11) : 6102 - 6106
  • [22] ONATE SA, 1995, SCIENCE, V270, P1354
  • [23] The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation
    Ricote, M
    Li, AC
    Willson, TM
    Kelly, CJ
    Glass, CK
    [J]. NATURE, 1998, 391 (6662) : 79 - 82
  • [24] Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase
    Rossi, A
    Kapahi, P
    Natoli, G
    Takahashi, T
    Chen, Y
    Karin, M
    Santoro, MG
    [J]. NATURE, 2000, 403 (6765) : 103 - 108
  • [25] Transactivation by retinoid X receptor peroxisome proliferator-activated receptor γ (PPARγ) heterodimers:: Intermolecular synergy requires only the PPARγ hormone-dependent activation function
    Schulman, IG
    Shao, G
    Heyman, RA
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1998, 18 (06) : 3483 - 3494
  • [26] 15-deoxy-Δ12,14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway
    Straus, DS
    Pascual, G
    Li, M
    Welch, JS
    Ricote, M
    Hsiang, CH
    Sengchanthalangsy, LL
    Ghosh, G
    Glass, CK
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (09) : 4844 - 4849
  • [27] Suh N, 1998, CANCER RES, V58, P717
  • [28] Suh NJ, 1999, CANCER RES, V59, P336
  • [29] Tang W., 1992, CHINESE DRUGS PLANT
  • [30] MPPAR-GAMMA-2 - TISSUE-SPECIFIC REGULATOR OF AN ADIPOCYTE ENHANCER
    TONTONOZ, P
    HU, E
    GRAVES, RA
    BUDAVARI, AI
    SPIEGELMAN, BM
    [J]. GENES & DEVELOPMENT, 1994, 8 (10) : 1224 - 1234