A novel transcriptional factor with Ser/Thr kinase activity involved in the transforming growth factor (TGF)-beta signalling pathway.
Transforming growth factor-beta (TGF-beta) shows a variety of biological activities in various organs or cells. Recently some factors such as Smads (Sma and Mad proteins) and TGF-beta activating kinase 1 ('TAK1') have been characterized as signalling molecules downstream of TGF-beta. Several TGF-beta response elements have been identified such as cAMP response element, Smad binding element, and recognition sites for activating protein-1 and stimulating protein-1 in various gene promoters. We also reported a TGF-beta response element in the human C-type natriuretic peptide (CNP) gene promoter. In this paper, we report on a novel factor which regulates the TGF-beta response promoter. This factor, named TSF1 (TGF-beta stimulated factor 1), possessed DNA-binding ability and activated the TGF-beta responsive CNP promoter or vascular endothelial growth factor gene promoter which possesses a sequence element analogous to the TGF-beta responsive GC-rich element of the CNP promoter. TSF1 did not directly activate a Smads-dependent promoter from plasminogen activator inhibitor 1 gene, but it showed enhancement in co-operation with Smad3 and Smad4. Interestingly, this factor had the structural features of a Ser/Thr kinase and actually exhibited protein kinase activity. TSF1 mRNA as well as its protein level were stimulated by TGF-beta treatment. Thus, TSF1 is an unique factor with two biological functions, transcriptional regulation and protein phosphorylation, that may be involved in TGF-beta signals.
Ohta
S
S
Shionogi Research Laboratories, Shionogi & Co. Ltd, 5-12-4Sagisu, Fukushima-ku, Osaka, Osaka 553-0002, Japan.
Takeuchi
M
M
Deguchi
M
M
Tsuji
T
T
Gahara
Y
Y
Nagata
K
K
D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000235:genetics; D004789:Enzyme Activation; D004926:Escherichia coli / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051900:Smad3 Protein; D051901:Smad4 Protein; D013997:Time Factors; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C497787:Smad3 protein, rat; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C490811:Smad4 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004247:DNA; D010770:Phosphotransferases; C486000:Stk16 protein, mouse; C486001:Stk16 protein, rat; D017346:Protein Serine-Threonine Kinases; C418980:STK16 protein, human