Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Cachexia / genetics
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Cytokines / genetics*
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Cytokines / pharmacology
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Feedback, Physiological*
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Gene Expression Regulation, Developmental*
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Genes, Lethal
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Inflammation / genetics
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Mice
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Mice, Knockout
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Mutation / genetics
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Promoter Regions, Genetic / genetics
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Protein Binding
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Signal Transduction / drug effects
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Skin / pathology
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Transcription Factor RelA
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Transcription Factors*
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Transcription, Genetic
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Transcriptional Activation
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Tumor Necrosis Factor-alpha / pharmacology
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Twist-Related Protein 1
Substances
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Cytokines
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NF-kappa B
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Nuclear Proteins
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Transcription Factor RelA
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Twist-Related Protein 1