Human T-cell lymphotropic virus type 1 tax inhibits transforming growth factor-beta signaling by blocking the association of Smad proteins with Smad-binding element.
The human T-cell lymphotropic virus type 1 (HTLV-1) oncoprotein Tax is implicated in various clinical manifestations associated with infection by HTLV-1, including an aggressive and fatal T-cell malignancy. Because many human HTLV-1-infected T-cell lines are resistant to the growth inhibitory activity of transforming growth factor beta (TGF-beta), we examined the possibility that the HTVL-1-Tax oncoprotein regulates TGF-beta signaling. We show that Tax significantly decreases transcriptional activity and growth inhibition in response to TGF-beta. Tax inhibits TGF-beta-induced plasminogen activator inhibitor-1 expression and Smad2 phosphorylation. Competitive interaction studies show that Tax inhibits TGF-beta signaling, in part, by disrupting the interaction of the Smads with the transcriptional co-activator p300. Tax directly interacts with Smad2, Smad3, and Smad4; the Smad MH2 domain binds to Tax. Furthermore, Tax inhibits Smad3.Smad4 complex formation and its DNA binding. These results suggest that suppression of Smad-mediated signaling by Tax may contribute to HTLV-1-associated leukemogenesis.
Lee
Dug Keun
DK
Laboratory of Cell Regulation and Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Kim
Byung-Chul
BC
Brady
John N
JN
Jeang
Kuan-Teh
KT
Kim
Seong-Jin
SJ
D001667:Binding, Competitive; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016356:Gene Products, tax / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology; D009687:Nuclear Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology
D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D009687:Nuclear Proteins; D012097:Repressor Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta