Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression.
Transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, is suggested to be involved in TGF-beta-induced gene expression, but the signaling mechanism from TAK1 to the nucleus remains largely undefined. We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. Expression of dominant negative MKK6 or dominant negative TAK1 inhibited the TGF-beta-induced transcriptional activation as well as the p38 activation. Constitutive activation of the p38 pathway in the absence of TGF-beta induced the transcriptional activation, which was enhanced synergistically by coexpression of Smad2 and Smad4 and was inhibited by expression of the C-terminal truncated, dominant negative Smad4. Furthermore, we have found that activating transcription factor-2 (ATF-2), which is known as a nuclear target of p38, becomes phosphorylated in the N-terminal activation domain in response to TGF-beta, that ATF-2 forms a complex with Smad4, and that the complex formation is enhanced by TGF-beta. In addition, expression of a nonphosphorylatable form of ATF-2 inhibited the TGF-beta-induced transcriptional activation. These results show that the p38 pathway is activated by TGF-beta and is involved in the TGF-beta-induced transcriptional activation by regulating the Smad-mediated pathway.
Hanafusa
H
H
Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Ninomiya-Tsuji
J
J
Masuyama
N
N
Nishita
M
M
Fujisawa
J
J
Shibuya
H
H
Matsumoto
K
K
Nishida
E
E
D051698:Activating Transcription Factor 2; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D016350:Leucine Zippers; D048669:MAP Kinase Kinase 6; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7
D051698:Activating Transcription Factor 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D048669:MAP Kinase Kinase 6; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C482566:MAP2K6 protein, human