Stress- and Rho-activated ZO-1-associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival.
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.
Department of Cell Biology, Institute of Ophthalmology,  University College London, London EC1V 9EL,  United Kingdom.
Mei
M
Nie
Maria S
MS
Balda
Karl
K
Matter
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D018938:Caco-2 Cells; D002470:Cell Survival / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000378:metabolism; D009336:Necrosis / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D020871:RNA Stability / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013314:Stress, Mechanical; D019108:Tight Junctions / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D062826:Zonula Occludens-1 Protein; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
C577356:ARHGEF2 protein, human; D022762:CCAAT-Enhancer-Binding Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020662:Guanine Nucleotide Exchange Factors; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D064067:Rho Guanine Nucleotide Exchange Factors; C569042:TJP1 protein, human; D014409:Tumor Necrosis Factor-alpha; C094867:YBX3 protein, human; D062826:Zonula Occludens-1 Protein; D020741:rho GTP-Binding Proteins