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Twist Regulates Cytokine Gene Expression through a Negative Feedback Loop that Represses NF-kB Activity

Twist Regulates Cytokine Gene Expression through a Negative Feedback Loop that Represses NF-kB Activity

Cell 112(2): 9-80

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-kB 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-kB-dependent cytokine pathway. Reprinted by permission of the publisher.

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