Tieg3/Klf11 induces apoptosis in OLI-neu cells and enhances the TGF-beta signaling pathway by transcriptional repression of Smad7.
TGF-beta signaling is indispensible for development of the nervous system since it regulates ontogenetic cell death. The recently identified TGF-beta-inducible zinc finger protein Tieg3/Klf11 belongs to the family of Sp1/Klf-like transcription factors and shares all structural and functional features with other Tieg proteins. Using the established TGF-beta-responsive oligodendroglial cell line OLI-neu, we analyzed the role of Tieg3/Klf11 in TGF-beta signaling. In this report, we show that Tieg3/Klf 11 mimics TGF-beta effects by inducing apoptotic cell death accompanied by activation of caspase-3. Moreover, we demonstrate that Tieg3/Klf11 enhances TGF-beta signaling by transcriptional repression of the inhibitory Smad7 and, thereby, disrupts the negative feedback loop of the TGF-beta signaling pathway. Loss of the N-terminal repression domains of Tieg3/Klf11 abrogates the pro-apoptotic nature of this transcription factor and abolishes the enhancement of Smad-mediated TGF-beta responses. In conclusion, we provide evidence that the recently identified transcription factor Tieg3/Klf11 is a downstream mediator of TGF-beta-induced apoptosis in the oligodendroglial cell line OLI-neu. Since other signaling molecules are able to initiate transcription of members of the Tieg family, the ability of Tieg3/Klf11 to modulate TGF-beta signaling by transcriptional inhibition of Smad7 might be an important clue for the understanding of the crosstalk between different signaling pathways.
Gohla
Gabriele
G
Department of Neuroanatomy, Center of Anatomy, Georg-August-University of Göttingen, Göttingen, Germany.
Krieglstein
Kerstin
K
Spittau
Björn
B
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins; D015398:Signal Transduction; D051906:Smad7 Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; C506460:KLF11 protein, mouse; D012097:Repressor Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053148:Caspase 3