The Role of Human Antigen R, an RNA-binding Protein, in Mediating the Stabilization of Toll-Like Receptor 4 mRNA Induced by Endotoxin

Lin, Feng Yen; Chen, Yung‐Hsiang; Lin, Yi Wen; Tsai, J S; Chen, Jaw Wen; Wang, Hsiao Jung; Chen, Yuh‐Lien; Li, Chi Yuan; Lin, Shing Jong

doi:10.1161/01.atv.0000246779.78003.cf

Cited by 71 publications

(60 citation statements)

References 38 publications

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“…Rac can also regulate mRNA stability, [26][27][28] and the cyclin D1 3'-UTR contains AU-rich elements which can recruit RNA stabilizing proteins. 29 We therefore determined the effect of Rac on the half-life of cyclin D1 mRNA.…”

Section: Resultsmentioning

confidence: 99%

NFκB-Independent Signaling to the Cyclin D1 Gene by Rac

et al. 2007

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AbbREviAtionsNFκB nuclear factor κB ERK extracellular signal-regulated kinase P-ERK dually phosphorylated ERK MEF mouse embryo fibroblast QPCR quantitative RT-PCR ACKnowlEdGEMEntsWe thank Jessie Villanueva and Hanqin Lei for generating some of the cyclin D1 promoterluciferase constructs described in this paper. This work was supported by NIH grants GM069064 and CA72639 to R.K.A. AbstRACtIn this report we characterize the mechanism of Rac-mediated cyclin D1 gene expression in mouse embryonic fibroblasts. Activated Rac strongly stimulated cyclin D1 gene transcription but did not alter the half-life of cyclin D1 mRNA. Inhibition of NFκB signaling with the IκB super-repressor blocked the Rac-dependent expression of cyclin D1 mRNA, and this effect was selective since ERK-dependent cyclin D1 mRNA induction was minimally affected by super-repressor expression. However, we found that p65 activity in this system was induced by serum and not by activated Rac. Moreover, mouse cyclin D1 promoter-luciferase assays showed that Rac stimulated cyclin D1 gene expression without activating NFκB and that an essential Rac-regulated promoter element is located far upstream or downstream of the cyclin D1 transcription start site. We conclude that, in MEFs, Rac-mediated induction of cyclin D1 mRNA requires activation of a parallel NFκB pathway whereas ERK induces cyclin D1 transcription independent of NFκB.

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Section: Resultsmentioning

confidence: 99%

NFκB-Independent Signaling to the Cyclin D1 Gene by Rac

et al. 2007

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“…The HuR is an RNA binding protein that enhances the stability of target mRNAs (26,27). It has been shown that activation of the p38 MAPK pathway results in the translocation of HuR from the nucleus to the cytoplasm where it binds to the 3 ¶-untranslated regions (UTR) of various mRNAs containing a core AUUUA sequence (20,(28)(29)(30)(31). The p75 NTR transcript contains two AUUUA sites in the 3 ¶-UTR, suggesting HuR binding as a possible mechanism by which Rflurbiprofen and ibuprofen may stabilize p75 NTR mRNA.…”

Section: R-flurbiprofen and Ibuprofen Increase P75mentioning

confidence: 99%

The p38 MAPK Pathway Mediates Aryl Propionic Acid–Induced Messenger RNA Stability of p75NTR in Prostate Cancer Cells

Quann¹,

Khwaja²,

Djakiew

2007

Cancer Research

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The p75 NTR acts as a tumor suppressor in the prostate, but its expression is lost as prostate cancer progresses and is minimal in established prostate cancer cell lines such as PC-3, DU-145, and LNCaP. Previously, we showed that treatment with R-flurbiprofen or ibuprofen induced p75 NTR expression in PC-3 and DU-145 cells leading to p75 NTR -mediated decreased survival. Here, we investigate the mechanism by which these drugs induce p75 NTR expression. We show that the observed increase in p75NTR protein due to R-flurbiprofen and ibuprofen treatment was accompanied by an increase in p75 NTR mRNA, and this increase in mRNA was the result of increased mRNA stability and not by an up-regulation of transcription. In addition, we show that treatment with R-flurbiprofen or ibuprofen led to sustained activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Furthermore, inhibition of the p38 MAPK pathway with the p38 MAPK-specific inhibitor SB202190 or by small interfering RNA (siRNA) knockdown of p38 MAPK protein prevented induction of p75 NTR by R-flurbiprofen and ibuprofen. We also observed that siRNA knockdown of MAPK-activated protein kinase (MK)-2 and MK3, the kinases downstream of p38 MAPK that are responsible for the mRNA stabilizing effects of the p38 MAPK pathway, also prevented an induction of p75 NTR by R-flurbiprofen and ibuprofen. Finally, we identify the RNA stabilizing protein HuR and the posttranscriptional regulator eukaryotic translation initiation factor 4E as two possible mechanisms by which the p38 MAPK pathway may increase p75 NTR expression. Collectively, the data suggest that R-flurbiprofen and ibuprofen induce p75 NTR expression by increased mRNA stability that is mediated through the p38 MAPK pathway. [Cancer Res 2007;67(23):11402-10]

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“…Moreover, siRNA knockdown of both MK2 and MK3 together prevents induction of p75 NTR by R-flurbiprofen or ibuprofen to a greater extent than knockdown of either MK2 or MK3 separately, indicating that p38 MAPK is able to induce p75 NTR by acting through both MK2 and MK3 (Quann et al, 2007b). The mRNA stabilizing effects of the p38 MAPK pathway (Ronkina et al, 2007) also involves the RNA binding protein HuR (Tran et al, 2003;Lin et al, 2006;Jin et al, 2007;Song et al, 2005). Its ability to stabilize target mRNAs is linked to its subcellular localization, and activation of p38 MAPK and MK2 have been shown to cause translocation of HuR from the nucleus to the cytoplasm, resulting in increased mRNA stability of a number of p38 MAPK regulated genes (Tran et al, 2003;Lin et al, 2006;Jin et al, 2007;Song et al, 2005).…”

Section: Nsaid Induced Phosphorylation Of P38 Mapk Is Necessary For Imentioning

confidence: 99%

“…The mRNA stabilizing effects of the p38 MAPK pathway (Ronkina et al, 2007) also involves the RNA binding protein HuR (Tran et al, 2003;Lin et al, 2006;Jin et al, 2007;Song et al, 2005). Its ability to stabilize target mRNAs is linked to its subcellular localization, and activation of p38 MAPK and MK2 have been shown to cause translocation of HuR from the nucleus to the cytoplasm, resulting in increased mRNA stability of a number of p38 MAPK regulated genes (Tran et al, 2003;Lin et al, 2006;Jin et al, 2007;Song et al, 2005). HuR has repeatedly been shown to stabilize transcripts containing the AUUUA sequence (Tran et al, 2003;Song et al, 2005).…”

Section: Nsaid Induced Phosphorylation Of P38 Mapk Is Necessary For Imentioning

confidence: 99%

NSAID Induction of p75NTR in the Prostate: A Suppressor of Growth and Cell Migration Via the p38 MAPK Pathway

Djakiew¹

2011

Prostate Cancer - Original Scientific Reports and Case Studies

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The Role of Human Antigen R, an RNA-binding Protein, in Mediating the Stabilization of Toll-Like Receptor 4 mRNA Induced by Endotoxin

Cited by 71 publications

References 38 publications

NFκB-Independent Signaling to the Cyclin D1 Gene by Rac

NFκB-Independent Signaling to the Cyclin D1 Gene by Rac

The p38 MAPK Pathway Mediates Aryl Propionic Acid–Induced Messenger RNA Stability of p75NTR in Prostate Cancer Cells

NSAID Induction of p75NTR in the Prostate: A Suppressor of Growth and Cell Migration Via the p38 MAPK Pathway

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