Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 27, Pages 10897-10902Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1118822109
Keywords
epithelia; RhoGTPases; tight junction; necrosis; apoptosis
Categories
Funding
- Biotechnology and Biological Sciences Research Council
- Wellcome Trust
- Medical Research Council
- BBSRC [BB/H002294/1] Funding Source: UKRI
- MRC [G0400678, G0900098, G0700743] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H002294/1] Funding Source: researchfish
- Medical Research Council [G0400678, G0700743, G0900098] Funding Source: researchfish
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A central component of the cellular stress response is p21(WAF1/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.
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