Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival
Edited by Keith Burridge, University of North Carolina, Chapel Hill, NC, and accepted by the Editorial Board May 22, 2012 (received for review November 15, 2011)
Abstract
A central component of the cellular stress response is p21WAF1/CIP1, which regulates cell proliferation, survival, and differentiation. Inflammation and cell stress often up-regulate p21 posttranscriptionally by regulatory mechanisms that are poorly understood. ZO-1–associated nucleic acid binding protein (ZONAB)/DbpA is a Y-box transcription factor that is regulated by components of intercellular junctions that are affected by cytokines and tissue damage. We therefore asked whether ZONAB activation is part of the cellular stress response. Here, we demonstrate that ZONAB promotes cell survival in response to proinflammatory, hyperosmotic, and cytotoxic stress and that stress-induced ZONAB activation involves the Rho regulator GEF-H1. Unexpectedly, stress-induced ZONAB activation does not stimulate ZONAB’s activity as a transcription factor but leads to the posttranscriptional up-regulation of p21 protein and mRNA. Up-regulation is mediated by ZONAB binding to specific sites in the 3′-untranslated region of the p21 mRNA, resulting in mRNA stabilization and enhanced translation. Binding of ZONAB to mRNA is activated by GEF-H1 via Rho stimulation and also mediates Ras-induced p21 expression. We thus identify a unique type of stress and Rho signaling activated pathway that drives mRNA stabilization and translation and links the cellular stress response to p21 expression and cell survival.
Acknowledgments
This research was supported by the Biotechnology and Biological Sciences Research Council, the Wellcome Trust, and the Medical Research Council.
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Cover image: Pictured are colloidal particles, each consisting of one sphere with a smooth surface and one sphere with a rough surface. Daniela J. Kraft et al. used colloidal particles with different surface roughnesses to create self-assembling colloidal micelles. Studying self-assembly processes at the colloidal scale could provide insights into how this assembly is controlled, and this knowledge could be used to construct complex structures with desirable chemical properties. See the article by Kraft et al. on pages 10787–10792. Image courtesy of Daniela J. Kraft.
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Published online: June 18, 2012
Published in issue: July 3, 2012
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Acknowledgments
This research was supported by the Biotechnology and Biological Sciences Research Council, the Wellcome Trust, and the Medical Research Council.
Notes
This article is a PNAS Direct Submission. K.B. is a guest editor invited by the Editorial Board.
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The authors declare no conflict of interest.
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