Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2

Kauppinen, Tiina M.; Chan, Wai Yee; Suh, Sang Won; Wiggins, Amanda K.; Huang, Eric J.; Swanson, Raymond A.

doi:10.1073/pnas.0508606103

Cited by 190 publications

(193 citation statements)

References 44 publications

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“…150 The MAPK/ ERK signaling pathway may also regulate inflammation through its effects on PARP-1 activation, which (as detailed later in this review) is an important modulator of proinflammatory gene expression. 151 Pharmacological inhibition of both the p38 152,153 and the MAPK/ERK 154 signaling pathways improves outcomes in a mouse model of ischemia-reperfusion, but the extent to which these effects are due to reduced inflammation has not been established.…”

Section: Mitogen-activated Protein Kinase (Mapk) Cascadementioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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Section: Mitogen-activated Protein Kinase (Mapk) Cascadementioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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“…Thus, it seems that dephosphorylation of PARP-1 by PP5 facilitates PARP-1 activity or PARP-1 activation. The work of other groups and our preliminary analysis indicates that PARP-1 is phoshosphorylated on many sites (Kauppinen et al, 2006, data not shown). It will be interesting to identify the specific sites that are dephosphorylated by PP5 and to determine how they affect PARP-1 activity.…”

Section: Discussionmentioning

confidence: 50%

“…It has been suggested previously that phosphorylation may regulate PARP-1 activity (Kauppinen et al, 2006;Midorikawa et al, 2006). As it seemed that neither ATM-initiated signaling nor DNA-PK influenced activation of PARP-1 in response …”

Section: Activation Of Parp-1 After Bleomycin Treatment Depends On Pp5mentioning

confidence: 95%

“…PARP-1 is a phosphoprotein and several studies have suggested that modulation of PARP-1 phosphorylation can regulate its activity (Tanaka et al, 1987;Bauer et al, 1992;Ju et al, 2004;Kauppinen et al, 2006;Midorikawa et al, 2006). For example, PARP-1 can be phosphorylated by protein kinase C, and phosphorylation of PARP-1 and PARP-1 interacting factors have been shown to regulate PARP-1 activity (Tanaka et al, 1987;Bauer et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Activation of PARP-1 in response to bleomycin depends on the Ku antigen and protein phosphatase 5

Fang¹,

Soubeyrand²,

Haché

2010

Oncogene

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Poly (ADP-ribose) polymerase-1 (PARP-1) has an important role in the cellular response to a broad spectrum of DNA lesions. PARP-1 is strongly activated in response to double-stranded DNA breaks (DSBs), yet its contribution to the DSB response is poorly understood. Here we used bleomycin, a radiomimetic that generates DSBs with high specificity to focus on the response of PARP-1 to DSBs. We report that the induction of PARP-1 activity by bleomycin depends on the Ku antigen, a nonhomologous-DNA-End-Joining factor and protein phosphatase 5 (PP5). PARP-1 activation in response to bleomycin was reduced over 10-fold in Ku-deficient cells, whereas its activation in response to U.V. was unaffected. PARP-1 activation was rescued by reexpression of Ku, but was refractory to manipulation of DNA-dependent protein kinase or ATM. Similarly, PARP-1 activation subsequent to bleomycin was reduced 2-fold on ablation of PP5 and was increased 5-fold when PP5 was overexpressed. PP5 seemed to act directly on PARP-1, as its basal phosphorylation was reduced on overexpression of PP5, and PP5 dephosphorylated PARP-1 in vitro. These results highlight the functional importance of Ku antigen and PP5 for PARP-1 activity subsequent to DSBs.

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“…Mechanisms underlying PARP1-mediated necroptotic cell death include cellular metabolic insufficiency (due to NAD and ATP depletion), PARinduced nuclear translocation of AIF (apoptosis inducing factor), and interference with prosurvival and prodeath signaling pathways [11,[17][18][19]. As for the latter, signaling routes mediated by MAP kinases have been shown to be intertwined with PARylation [20][21][22][23]. Of note, it has been shown that the expression of MAP kinase phosphatase 1 (MKP-1) is negatively regulated by PARP1 strengthening prodeath pathways mediated by JNK and p38 MAP kinases [24].…”

Section: Introductionmentioning

confidence: 99%

The role of p38 signaling and poly(ADP-ribosyl)ation-induced metabolic collapse in the osteogenic differentiation-coupled cell death pathway

Robaszkiewicz

Valkó

Kovács

et al. 2014

Free Radical Biology and Medicine

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a b s t r a c tOsteogenic differentiation is a multistep process regulated by a diverse set of morphogenic and transcription factors. Previously we identified endogenous hydrogen peroxide-induced poly(ADP-ribose) polymerase-1 (PARP1) activation as a mediator of osteodifferentiation and associated cell death. Here we set out to investigate whether or not activation of PARP1 is dependent on DNA breaks and how PARP1 mediates cell death during osteodifferentiation of mesenchymal stem cells and SAOS-2 cells. Here we show that the MAP kinases p38, JNK, and ERK1/2 become activated during the differentiation process. However, only p38 activation depended both on hydrogen peroxide production and on PARP1 activation as the hydrogen peroxide decomposing enzyme catalase, the PARP inhibitor PJ34, and the silencing of PARP1 suppressed p38 activation. Inhibition of p38 suppressed cell death and inhibited osteogenic differentiation (calcium deposition, alkaline phosphatase activity, and marker gene expression) providing further support for the close coupling of osteodifferentiation and cell death. Metabolic collapse appears to be central in the hydrogen peroxide-PARP1-p38 pathway as silencing PARP1 or inhibition of p38 prevented differentiation-associated loss of cellular NAD, inhibition of mitochondrial respiration, and glycolytic activity. We also provide evidence that endogenous hydrogen peroxide produced by the differentiating cells is sufficient to cause detectable DNA breakage. Moreover, p38 translocates from the cytoplasm to the nucleus where it interacts and colocalizes with PARP1 as detected by immunoprecipitation and immunofluorescence, respectively. In summary, hydrogen peroxide-induced PARP1 activation leads to p38 activation and this pathway is required both for the successful completion of the differentiation process and for the associated cell death.

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Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2

Cited by 190 publications

References 44 publications

Microglial Activation in Stroke: Therapeutic Targets

Microglial Activation in Stroke: Therapeutic Targets

Activation of PARP-1 in response to bleomycin depends on the Ku antigen and protein phosphatase 5

The role of p38 signaling and poly(ADP-ribosyl)ation-induced metabolic collapse in the osteogenic differentiation-coupled cell death pathway

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