Synthetic triterpenoids enhance transforming growth factor beta/Smad signaling.
We have studied the effects of two new synthetic triterpenoids, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivative, 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole (CDDO-Im), on transforming growth factor (TGF)-beta/Smad signaling. These agents, at nanomolar concentrations, increase the expression of TGF-beta-dependent genes, such as those for plasminogen activator inhibitor 1 and the type II TGF-beta receptor, and they synergize with TGF-beta in this regard. They prolong the activation of Smad2 induced by TGF-beta and markedly enhance the ability of Smad3 to activate a Smad binding element, CAGA-luciferase. In transfection assays, they reverse the inhibitory effects of Smad7. CDDO and CDDO-Im also enhance Smad signaling in the pathways of two other members of the TGF-beta superfamily, namely, activin and bone morphogenetic protein. Finally, these triterpenoids induce expression of the transcriptional coactivator p300-CBP-associated factor and synergize with TGF-beta in this regard. These are the first studies to report enhancement of Smad signaling by synthetic triterpenoids and should further their optimal use for applications in prevention or treatment of diseases in which there is aberrant function of TGF-beta.
Suh
Nanjoo
N
Dartmouth Medical School and Dartmouth College, Hanover, New Hampshire 03755, USA.
Roberts
Anita B
AB
Birkey Reffey
Stephanie
S
Miyazono
Kohei
K
Itoh
Susumu
S
ten Dijke
Peter
P
Heiss
Elke H
EH
Place
Andrew E
AE
Risingsong
Renee
R
Williams
Charlotte R
CR
Honda
Tadashi
T
Gribble
Gordon W
GW
Sporn
Michael B
MB
D000123:Acetyltransferases / Q000096:biosynthesis; D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004357:Drug Synergism; D051548:Histone Acetyltransferases; D007093:Imidazoles / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008907:Mink; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein; D051906:Smad7 Protein; D013729:Terpenes / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014315:Triterpenes / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D007093:Imidazoles; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D009828:Oleanolic Acid; D017395:Plasminogen Activator Inhibitor 1; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051906:Smad7 Protein; D013729:Terpenes; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014315:Triterpenes; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; C497783:Smad2 protein, mouse; C497807:Smad7 protein, mouse; C508961:Tgfb1 protein, mouse; C496317:Nos2 protein, mouse