Y-box protein-1 is the crucial mediator of antifibrotic interferon-gamma effects - PubMed (original) (raw)

. 2006 Jan 20;281(3):1784-95.

doi: 10.1074/jbc.M510215200. Epub 2005 Nov 8.

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Y-box protein-1 is the crucial mediator of antifibrotic interferon-gamma effects

Steven Dooley et al. J Biol Chem. 2006.

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Abstract

Y-box protein-1 (YB-1) is a known negative regulator of collagen (Col) expression by two different mechanisms, acting directly through binding to an interferon-gamma response element within the col1A2 promoter and/or by physically interacting with p300/Smad3, thereby abrogating the stimulatory effect of transforming growth factor-beta (TGF-beta). Here, we report that YB-1 activation via the Jak1 signaling pathway is required and sufficient to confer interferon-gamma-dependent activation of the smad7 gene. By binding to a bona fide recognition site within the smad7 promoter, YB-1 up-regulates smad7 transcription, which was additively enhanced by autoinhibitory TGF-beta signaling. Importantly, the anti-TGF-beta effect was not only supplied by induced Smad7 expression but was recapitulated in the context of the col1A2 promoter, where YB-1 overexpression abolished the trans-stimulatory TGF-beta effect in a dominant fashion. In conclusion, YB-1 is the main target of interferon-gamma signaling via Jak1 that exerts antifibrotic action by both interference with TGF-beta signaling and direct down-regulation of collagen expression.

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