Ras effector pathways modulate scatter factor-stimulated NF-κB signaling and protection against DNA damage

Fan, Saijun; Meng, Qinghui; Laterra, John; Rosen, Eliot M.

doi:10.1038/sj.onc.1210271

Cited by 25 publications

(24 citation statements)

References 58 publications

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“…Ras activation inhibits ZONAB's function as a transcription factor by inducing the formation of cytoplasmic complexes between activated RalA and ZONAB (21). RalA is activated by different types of stress and transmits cytokine-induced signals; hence, RalA activation seems to be a general mechanism to switch off the transcriptional activity of ZONAB (42)(43)(44)(45). However, Ral signaling does not affect ZONAB's posttranscriptional activity.…”

Section: Discussionmentioning

confidence: 99%

Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

Nie

Balda

Matter

2012

Proc. Natl. Acad. Sci. U.S.A.

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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.epithelia | RhoGTPases | tight junction | necrosis | apoptosis C ells developed regulatory pathways that are activated in response to proinflammatory challenges, adverse extracellular conditions, and cytotoxic stress to ensure cell survival and tissue integrity. These pathways regulate expression of genes encoding factors required to cope with stress conditions and involve transcription factors that stimulate the synthesis of mRNAs encoding proteins required for specific responses. However, expression of many crucial stress-induced genes is regulated posttranscriptionally by mechanisms that are not well understood.A central regulator of cell proliferation and survival is p21 WAF1/CIP1

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Section: Discussionmentioning

confidence: 99%

Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

Nie

Balda

Matter

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Downstream from p53, Ras or Raf activation by HB-EGF is responsible for the ERK-mediated induction of the cyclooxygenase-2 gene, which inhibits genotoxic stressinduced apoptosis (Han et al, 2002). Scatter Factor (hepatocyte growth factor), another growth factor that protects tumors from genotoxicity, uses Raf to signal survival through activation of nuclear factor-kB (Fan et al, 2007). In addition, an interplay between oncogenic Raf/ERK and ATM has been shown to promote homologous recombination repair in response to radiation (Golding et al, 2007), in line with previous reports showing a correlation between oncogenic Raf and radioresistance in tumors (Kasid et al, 1987(Kasid et al, , 1989(Kasid et al, , 1996.…”

Section: Evasion Of Senescence and Apoptosismentioning

confidence: 99%

Raf kinases in cancer–roles and therapeutic opportunities

2011

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Raf are conserved, ubiquitous serine/protein kinases discovered as the cellular elements hijacked by transforming retroviruses. The three mammalian RAF proteins (A, B and CRAF) can be activated by the human oncogene RAS, downstream from which they exert both kinase-dependent and kinase-independent, tumor-promoting functions. The kinase-dependent functions are mediated chiefly by the MEK/ERK pathway, whose activation is associated with proliferation in a broad range of human tumors. Almost 10 years ago, activating BRAF mutations were discovered in a subset of human tumors, and in the past year treatment with small-molecule RAF inhibitors has yielded unprecedented response rates in melanoma patients. Thus, Raf qualifies as an excellent molecular target for anticancer therapy. This review focuses on the role of BRAF and CRAF in different aspects of carcinogenesis, on the success of molecular therapies targeting Raf and the challenges they present.

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“…We identified MKK3 and MKK6 (activators of p38 (26,38)) as mediators of SF activation of NF-B in DU-145 and MDCK cells (48). Inhibition of p38 blocked SF-stimulated NF-B activity, suggesting that p38 is the relevant target of MKK3/6.…”

Section: Discussionmentioning

confidence: 99%

Role of Src Signal Transduction Pathways in Scatter Factor-mediated Cellular Protection

Fan

Meng

Laterra

et al. 2009

Journal of Biological Chemistry

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Ras effector pathways modulate scatter factor-stimulated NF-κB signaling and protection against DNA damage

Cited by 25 publications

References 58 publications

Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

Raf kinases in cancer–roles and therapeutic opportunities

Role of Src Signal Transduction Pathways in Scatter Factor-mediated Cellular Protection

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