The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest

Llopis, Alba; Salvador, Noelia; Ercilla, Amaia; Guaita‐Esteruelas, Sandra; Barrantes, Iván del Barco; Gupta, J. R. P.; Gaestel, Matthias; Davis, Roger J.; Nebreda, Ángel R.; Agell, Neus

doi:10.4161/cc.21917

Cited by 31 publications

(35 citation statements)

References 48 publications

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“…Activation of the kinase ATR prevents formation of DSBs in response to replication stress 26 . To assess whether NEAT1 paraspeckles modulate this critical survival pathway, we knocked down NEAT1 in U2OS cells in which replication fork stalling was exacerbated by hydroxyurea (HU), an agent that blocks DNA synthesis 27 . ATR signaling was compromised in NEAT1 and NEAT1_2 knockdown (KD) cells exposed to HU, as evidenced by a decrease in ATR-mediated phosphorylation of checkpoint kinase CHK1 at S345 and replication protein RPA32 at S33 (Fig.…”

Section: Neat1 Depletion Causes Replication Stressmentioning

confidence: 99%

p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity

Adriaens

Standaert

Barra

et al. 2016

Nat Med

400

425

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In a search for mediators of the p53 tumor suppressor pathway, which induces pleiotropic and often antagonistic cellular responses, we identified the long noncoding RNA (lncRNA) NEAT1. NEAT1 is an essential architectural component of paraspeckle nuclear bodies, whose pathophysiological relevance remains unclear. Activation of p53, pharmacologically or by oncogene-induced replication stress, stimulated the formation of paraspeckles in mouse and human cells. Silencing Neat1 expression in mice, which prevents paraspeckle formation, sensitized preneoplastic cells to DNA-damage-induced cell death and impaired skin tumorigenesis. We provide mechanistic evidence that NEAT1 promotes ATR signaling in response to replication stress and is thereby engaged in a negative feedback loop that attenuates oncogene-dependent activation of p53. NEAT1 targeting in established human cancer cell lines induced synthetic lethality with genotoxic chemotherapeutics, including PARP inhibitors, and nongenotoxic activation of p53. This study establishes a key genetic link between NEAT1 paraspeckles, p53 biology and tumorigenesis and identifies NEAT1 as a promising target to enhance sensitivity of cancer cells to both chemotherapy and p53 reactivation therapy.

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Section: Neat1 Depletion Causes Replication Stressmentioning

confidence: 99%

p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity

Adriaens

Standaert

Barra

et al. 2016

Nat Med

400

425

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show abstract

“…Noteworthy, Ser139 phosphorylation of H2AX is not exclusively mediated by the PI3-like kinases ATM/ATR/DNA-PKcs but can also be catalyzed for instance by JNK/SAPK [59]. JNK and p38 kinase have been shown to influence replication stress-associated checkpoint control mechanisms [66]. Recently it has been reported that protein phosphatase 2A (PP2A) is able to antagonize ATR-regulated Chk1 phosphorylation [67,68].…”

Section: Influence Of Lovastatin On Ir-and Doxo-stimulated Mechanismsmentioning

confidence: 98%

Lovastatin protects keratinocytes from DNA damage-related pro-apoptotic stress responses stimulated by anticancer therapeutics

Ziegler

Albers

Fritz

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Interestingly, p38 MAPK and Chk1 were found to work cooperatively to activate G 2 /M arrest (Hirose et al, 2004;Llopis et al, 2012). Both pathways were shown to deactivate CDC25C in response to TMZ treatment, resulting in CDK1 inactivation and G 2 /M arrest in U87 glioblastoma cells.…”

Section: The Therapeutic Potential Of Targeting Mk2mentioning

confidence: 99%

Mitogen-Activated Protein Kinase–Activated Protein Kinase 2 in Neuroinflammation, Heat Shock Protein 27 Phosphorylation, and Cell Cycle: Role and Targeting

2013

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Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAPK-2 or MK2) is a downstream substrate of the p38 MAPK responsible for the signaling events influencing inflammation, cell division and differentiation, apoptosis, and cell motility in response to a wide range of extracellular stimuli. After the failure of p38 MAPK inhibitors in clinical trials, MK2 was unveiled as a potential target to regulate inflammatory cytokines' mRNA stability and translation. Recent work suggests that this mechanism may underlie the pathophysiology of brain disorders associated with inflammation. In addition, MK2 is a prominent kinase that phosphorylates heat shock protein 27 (Hsp27), an intensively investigated biomarker of cancer progression. This phosphorylation decreases the chaperone properties of Hsp27, making MK2 an endogenous inhibitor of Hsp27. MK2 is also one of the major players in the signal transduction pathways activated in response to DNA damage. Experimental evidence highlights the role of MK2 in G 2 /M and the mitotic spindle checkpoints, two mechanisms by which MK2 contributes to the maintenance of genomic stability. Thus, MK2 is considered a good molecular target to increase, in combination with chemotherapeutic agents, the sensitivity of treatment, especially in p53-mutated tumors. This review looks at the functions of MK2 in inflammation, Hsp27 regulation, and cell cycle checkpoint control with a focus on brain pathologies. Analysis of MK2 signaling in various disease models and a summary of the data on MK2 inhibitors suggest novel indications for MK2 inhibitors in addition to their mainstream use against peripheral inflammatory disorders.

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The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest

Cited by 31 publications

References 48 publications

p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity

p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity

Lovastatin protects keratinocytes from DNA damage-related pro-apoptotic stress responses stimulated by anticancer therapeutics

Mitogen-Activated Protein Kinase–Activated Protein Kinase 2 in Neuroinflammation, Heat Shock Protein 27 Phosphorylation, and Cell Cycle: Role and Targeting

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