Transcriptional regulation of Smad2 is required for enhancement of TGFbeta/Smad signaling by TGFbeta inducible early gene.
TGFbeta inducible early gene (TIEG) is a novel Krüppel-like transcriptional repressor that was recently shown to increase the activity of the TGFbeta/Smad signal transduction pathway by relieving negative feedback through repression of the inhibitory Smad7. Interestingly, while Smad7 is required for maximal enhancement of TGFbeta/Smad signaling, we observe that TIEG is still capable of increasing Smad pathway activity in the absence of Smad7. Furthermore, while Smad7 is known to block both TGFbeta and bone morphogenetic protein (BMP) signaling, we observe that TIEG specifically enhances only the TGFbeta pathway. Similarly, while both TIEG and the related Krüppel-like factor, FKLF2, repress Smad7 transcription, only TIEG is capable of enhancing Smad signaling. In order to identify additional regulatory targets of TIEG important for this enhancement of the Smad pathway activity, we performed microarray analysis and identified Smad2 as a TIEG target gene. We now show evidence that TIEG increases transcription of the Smad2 gene but not the Smad3 or Smad4 genes. Furthermore, while the TGFbeta/Smad pathway remains intact in Smad2 null cells, TIEG enhancement of Smad signaling is dramatically reduced. Thus we propose a new model whereby TIEG enhances Smad signaling by a dual mechanism involving both the repression of the inhibitory Smad7 as well as the activation of Smad2.
Johnsen
Steven A
SA
Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Subramaniam
Malayannan
M
Katagiri
Takenobu
T
Janknecht
Ralf
R
Spelsberg
Thomas C
TC
D000818:Animals; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta