TGFbeta inducible early gene enhances TGFbeta/Smad-dependent transcriptional responses.
TGFbeta inducible early gene (TIEG) encodes a three zinc-finger Krüppel-like transcription factor whose overexpression has been shown to mimic the effects of TGFbeta in human osteosarcoma and pancreatic carcinoma cells. In order to investigate a potential role of TIEG in the TGFbeta signal transduction pathway, we studied its impact on a Smad binding element (SBE) reporter which is known to be regulated by TGFbeta through the R-Smad proteins. We demonstrate that TIEG overexpression enhances TGFbeta induction of SBE reporter activity. TIEG overexpression also enhances induction of the endogenous TGFbeta regulated genes p21 and PAI-1. The ability of TIEG to enhance TGFbeta actions is Smad dependent since TIEG has no effect on SBE transcription in the absence of Smad4 expression or when an inhibitory Smad protein, Smad7, is overexpressed. Furthermore, TIEG overexpression enhances TGFbeta induced Smad2 phosphorylation. Lastly, TIEG appears to function by binding to and thereby repressing a specific element in the proximal promoter of the inhibitory Smad7 gene. In conclusion, these results describe a novel mechanism for the potentiation of TGFbeta/Smad signaling via repression of the inhibitory Smad7 gene by TIEG.
Johnsen
Steven A
SA
Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota, MN 55905, USA.
Subramaniam
Malayannan
M
Janknecht
Ralf
R
Spelsberg
Thomas C
TC
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051765:Early Growth Response Transcription Factors; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D051899:Smad2 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D051765:Early Growth Response Transcription Factors; C098111:KLF10 protein, human; D051741:Kruppel-Like Transcription Factors; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta