p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21<sup>Cip1</sup> mRNA Mediates the G<sub>1</sub>/S Checkpoint

Lafarga, Vanesa; Cuadrado, Ana; Silanes, Isabel López de; Bengoechea, Rocío; Fernández-Capetillo, Óscar; Nebreda, Ángel R.

doi:10.1128/mcb.00210-09

Cited by 222 publications

(230 citation statements)

References 52 publications

(63 reference statements)

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“…N, naïve; A, activated. mRNA stability (38,41). In addition, p38 has been shown to promote Xbp-1s mRNA stability and Xbp-1 protein nuclear translocation (44).…”

Section: Discussionmentioning

confidence: 99%

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The Serine-threonine Kinase Inositol-requiring Enzyme 1α (IRE1α) Promotes IL-4 Production in T Helper Cells

Kemp

Lin²,

Zhao³

et al. 2013

Journal of Biological Chemistry

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Background: IRE1␣ is a kinase important for the misfolded protein response. Results: IRE1␣ promotes IL-4 production by stabilizing IL-4 mRNA, and IRE1␣-specific inhibitor 48C suppresses IL-4 production. Conclusion: IRE1␣ is a positive regulator of IL-4 production by T helper cells. Significance: Cytokine IL-4 has been implicated in allergic response. Our discovery that IRE1␣ promotes IL-4 production implies that IRE1␣ inhibition has a therapeutic potential in allergic disease treatment.

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“…N, naïve; A, activated. mRNA stability (38,41). In addition, p38 has been shown to promote Xbp-1s mRNA stability and Xbp-1 protein nuclear translocation (44).…”

Section: Discussionmentioning

confidence: 99%

“…MAP kinase p38 activates mRNA binding protein HuR, and HuR promotes IL-4 mRNA stability (40,41). Therefore, we measured p38 phosphorylation upon TCR activation in IRE1␣ KO T cells to determine whether reduced IL-4 mRNA stability is due to reduced p38 activation.…”

Section: Volume 288 • Number 46 • November 15 2013mentioning

confidence: 99%

The Serine-threonine Kinase Inositol-requiring Enzyme 1α (IRE1α) Promotes IL-4 Production in T Helper Cells

Kemp

Lin²,

Zhao³

et al. 2013

Journal of Biological Chemistry

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“…AliouatDenis et al (2005) reported a p53-independent role for Chk2 in p21 induction and senescence. Moreover, the p38MAPK checkpoint pathway that regulates G2/M has recently been shown to regulate p21 function at the G1/S checkpoint in a p53-independent pathway (Lafarga et al, 2009). Considering the cross-talk between ATR and ATM pathways, and that replication stress and single-strand breaks may also lead to ATM activation (Ewald et al, 2007), it appears likely that p21 activation via p53-dependent or -independent mechanisms may hinder apoptosis induced by Chk1 inhibitors.…”

Section: Dna Damage Induced Apoptosis and Role Of Chk1mentioning

confidence: 99%

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

et al. 2010

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“…In fact, it was recently demonstrated that HuR is a direct substrate of p38 MAPK and that p38-dependent phosphorylation of HuR enhances its mRNA stabilizing activity (36).…”

Section: Hur Is a Crucial Regulator Of Uvb-induced Cox-2 Expression-tmentioning

confidence: 99%

Role of HuR and p38MAPK in Ultraviolet B-induced Post-transcriptional Regulation of COX-2 Expression in the Human Keratinocyte Cell Line HaCaT

Fernau

Fugmann

Leyendecker

et al. 2010

Journal of Biological Chemistry

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COX-2 (cyclooxygenase-2) is a pivotal player in inflammatory processes, and ultraviolet radiation is a known stimulus for COX-2 expression in skin cells. Here, an induction of COX-2 expression in HaCaT human keratinocytes was observed only upon exposure of cells to UVB (280 -320 nm) but not to UVA radiation (320 -400 nm), as demonstrated by reverse transcription-PCR and Western blotting. Prostaglandin E 2 levels were elevated in cell culture supernatants of HaCaT cells exposed to UVB. COX-2 mRNA stability was dramatically increased by UVB irradiation. Both the stabilization of COX-2 mRNA and the enhancement of COX-2 steady-state mRNA and protein levels caused by UVB were prevented both by inhibition and small interfering RNA-induced depletion of p38 MAPK , a kinase strongly activated upon exposure to UVB, suggesting p38 MAPK -dependent mRNA stabilization as a mechanism of UVB-induced COX-2 expression. A dramatic decrease in COX-2 expression induced by UVB was elicited by small interfering RNA-based depletion of a stress-responsive mRNA stabilizing protein regulated by p38 MAPK , i.e. HuR; UVB-induced elevation of COX-2 mRNA and protein levels coincided with an accumulation of HuR in the cytoplasm and was attenuated in cells depleted of HuR. Moreover, UVB-induced generation of prostaglandin E 2 by HaCaT cells was blunted by HuR depletion, suggesting that stress kinases (such as p38 MAPK ) as well as HuR are excellent targets for approaches aiming at interfering with induction of COX-2 expression by UVB.Cyclooxygenases catalyze the rate-limiting step in prostaglandin biosynthesis, i.e. the conversion of arachidonic acid to prostaglandin (PG) 3 H 2 , which in turn is converted by various synthases to different prostaglandins or thromboxane A 2 , important mediators in inflammatory processes. Two genes coding for isoforms of cyclooxygenase (COX-1 and COX-2) are known (1). Although COX-1 and a COX-1 variant, termed COX-3 (2), are constitutively expressed, expression of COX-2 is strongly inducible by growth factors, cytokines, and other stimuli, resulting in the production of prostaglandins during inflammatory processes. One such potent stimulus for COX-2 induction is UV radiation. Both UVB (280 -320 nm) (3) and UVA (320 -400 nm) (4) were reported previously to enhance the expression of COX-2 in human keratinocytes, followed by an increased production of the inflammatory mediator PGE 2 , a major prostaglandin in skin. Analysis of the relative contributions of UV ranges to the effects of solar light on COX-2 levels demonstrated that UVB is a far more efficient inducer of COX-2 expression; for example, UVB and UVA-2 (320 -350 nm) but not UVA-1 (350 -400 nm) contributed to COX-2 induction by simulated solar light in artificial human epidermis (5). Several lines of evidence link COX-2 and PGE 2 to the development of UV-induced skin cancer, such as the findings that COX-2 and PGE 2 levels are elevated in skin cancer versus normal tissue, that PGE 2 is a promoting factor in skin carcinogenesis, and that depletion or inhib...

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p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21^Cip1 mRNA Mediates the G₁/S Checkpoint

Cited by 222 publications

References 52 publications

The Serine-threonine Kinase Inositol-requiring Enzyme 1α (IRE1α) Promotes IL-4 Production in T Helper Cells

The Serine-threonine Kinase Inositol-requiring Enzyme 1α (IRE1α) Promotes IL-4 Production in T Helper Cells

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

Role of HuR and p38MAPK in Ultraviolet B-induced Post-transcriptional Regulation of COX-2 Expression in the Human Keratinocyte Cell Line HaCaT

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p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21Cip1 mRNA Mediates the G1/S Checkpoint

Cited by 222 publications

References 52 publications

The Serine-threonine Kinase Inositol-requiring Enzyme 1α (IRE1α) Promotes IL-4 Production in T Helper Cells

The Serine-threonine Kinase Inositol-requiring Enzyme 1α (IRE1α) Promotes IL-4 Production in T Helper Cells

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

Role of HuR and p38MAPK in Ultraviolet B-induced Post-transcriptional Regulation of COX-2 Expression in the Human Keratinocyte Cell Line HaCaT

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p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21^Cip1 mRNA Mediates the G₁/S Checkpoint