Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity.
During Drosophila embryogenesis, the dorsal transcription factor activates the expression of twist, a transcription factor required for mesoderm formation. We show here that the mammalian twist proteins, twist-1 and -2, are induced by a cytokine signaling pathway that requires the dorsal-related protein RelA, a member of the NF-kappaB family of transcription factors. Twist-1 and -2 repress cytokine gene expression through interaction with RelA. Mice homozygous for a twist-2 null allele or doubly heterozygous for twist-1 and -2 alleles show elevated expression of proinflammatory cytokines, resulting in perinatal death from cachexia. These findings reveal an evolutionarily conserved signaling circuit in which twist proteins regulate cytokine signaling by establishing a negative feedback loop that represses the NF-kappaB-dependent cytokine pathway.
Šošić
Drazen
D
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Richardson
James A
JA
Yu
Kai
K
Ornitz
David M
DM
Olson
Eric N
EN
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002100:Cachexia / Q000235:genetics; D016207:Cytokines / Q000235:genetics* / Q000494:pharmacology; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D007249:Inflammation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000473:pathology; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051879:Twist-Related Protein 1
D016207:Cytokines; D016328:NF-kappa B; D009687:Nuclear Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051879:Twist-Related Protein 1