Pbktopk promotes tumour cell proliferation through p38 mapk. A role for the p38 mitogenactivated protein kinase. The p38 mapk pathway activation is triggered by a variety of stimuli, including uv damage, oxidative stress, and exposure to dna damaging agents, as well as growth factors and cytokines 7,8. Kinase regulates the dna damage response and drives. Effect of silver nanoparticles on mitogenactivated.
The change in phosphorylation status of endogenous xrcc1 after kinase inhibitor treatment prompted us to investigate the. Tegdmainduced oxidative dna damage and activation of atm. The increases in activation of the p38 mapk signaling and dna damage response pathways as a result of huinduced oxidative and replication stress suggest that these pathways may serve as intracellular effectors of the embryonic stress response. In this study, we have found that the p38 mitogenactivated protein kinase mapk plays a key role in the activation of p53 by genotoxic stress when provoked by chemotherapeutic agents.
In the following sections we will discuss a series of studies that describes the p38 mapk signaling pathway, dna damage and its response, possible role of p38 mapk pathway in dna damage response ddr in p53 mutated or compromised state, activation of p38 mapk pathway by dysfunctional telomeres and p38 mapk as a possible drug target. The p38 mitogenactivated protein kinase augments nucleotide. We show here that activation of p38 mapk by stimuli that induce dna double strand breaks dsbs, but not other stimuli, leads to its nuclear translocation. Rasmapk signaling functions in oxidative stress, dna. Tao kinases are activated acutely by ionizing radiation, ultraviolet radiation, and hydroxyurea. Effect of silver nanoparticles on mitogenactivated protein. Fulllength and truncated fragments of dominant negative taos inhibit the activation of p38 by dna damage. Mice treated withthe p38 mapk inhibitor sb202190 are protected against.
Thus, it appears that in addition to the atmdependent pathway other not yet established mechanisms activate p38 mapk in response to dna damage. Thus, nuclear localization of p38 mapk in response to dna damage inducing stimuli is associated with its phosphorylation. In addition, p38 kinase activation is induced by dna crosslinking agents and is sustained for more than a few days, triggering the apoptotic cascade 33,6264. Ikarugamycin induces dna damage, intracellular calcium. The change in phosphorylation status of endogenous xrcc1 after. Atr is recruited to sites of dna damage that are characterised by extended singlestranded ss dna coated with replication protein a rpa. Recruitment of additional proteins, such as rad9containing complexes, are required for activation of atr and subsequent phosphorylation of. Dec 11, 2006 pbktopk promotes tumour cell proliferation through p38 mapk activity and regulation of the dna damage response. Persistent activation of the rafmekerk pathway leads to accumulation of ros and dna damage, which activate the stressinduced mkk36 p38 pathway.
In response to genotoxic stress, dna damage checkpoints and repair pathways are activated that ensure dna is transmitted intact. Sustained activation of jnkp38 mapk pathways in response. To identify potential harmful effects of silver nanoparticles agnps on human health, a comprehensive toxicity assay was conducted on human jurkat t cells, using oxidative stressrelated endpoint. Mitogenactivated protein kinase 14, also called p38. Increase, oxidative stress activation, pmk1 p38 mapk leads to increased, dna damage repair february 15, 2017 03. Activation of p38 by atm may act as an alternative pathway in p53 mutated state. Atr, chk1, g2 phase, p38, uv introduction after genotoxic stress dna damage checkpoint and repair pathways are activated that ensure an in tact transmission of the dna hoeijmakers, 2001.
Hyperproliferative signals generated by activated mekerk may cause hyperreplication of dna, generating dna damage that is known to activate p38 ink4a and induce senescence 9,10,33. Generally, ddr is characterized by activation of ataxiatelangiectasia mutated kinase atm and formation of dnadamage foci, containing. Uvinduced g2 checkpoint depends on p38 mapk and minimal. The selective nuclear accumulation of p38 mapk in response to dna damage could be a mechanism to facilitate the phosphorylation of p38 mapk nuclear targets for the. Although p38 mapk inhibitor scio469 scios inc, ca, usa alone did not induce significant growth inhibition, it blocked baseline and ps341triggered phosphorylation of p38 mapk. Of note, the involvement of ros and dna damage in the sequential activation of the erk and p38 pathways may not be mutually exclusive, because ros is a known dna damaging agent.
Sustained activation of jnkp38 mapk pathways in response to. Emerging roles of the p38 mapk and pi3kaktmtor pathways in. The dna damage response involves a cascade of signalling events, mediated by serinethreonine protein kinases, which act on their substrates to enforce the biological output of the ddr. Pdf the role of p38 mapk pathway in p53 compromised. Dna damage induces the nuclear translocation of p38 mapk. Once activated, p38 binds to atp at its atpbinding site adenosine pocket to transfer the. We demonstrate that in nih 3t3 cells, p38 can be potently activated by drugs that cause dna damage by either promoting the formation of dna adducts or inhibiting topoisomerase ii, but not by therapeutically relevant doses of. In certain contexts, where persistent dna damage is present, p38 can promote cellular senescence and sasp expression 17, 24, 31. While mir34c is induced by p53 following dna damage, we show that in cells lacking p53 this is achieved by an alternative pathway which involves p38 mapk signalling to mk2. Ikarugamycin induces dna damage, intracellular calcium increase, p38 map kinase activation and apoptosis in hl60 human promyelocytic leukemia cells.
Mar 29, 2007 here we show that the tao kinases mediate the activation of p38 in response to various genotoxic stimuli. Atrdependent activation of p38 mapk is responsible for induction of apoptosis in cdc7depleted cellsbecause the activation of p38 mapk was a specific response to cdc7 depletion, we searched for upstream effectors of the p38 mapk. Hydroxyurea exposure triggers tissuespecific activation. Stressspecific p38 mapk activation is sufficient to drive. Indeed, depletion or inhibition of mapkactivated protein kinase 2 mk2 and mk3, which function downstream of p38, abolished phosphorylation. The oxidative dna damage observed was transient, likely due to dna repair. We fail to detect egfr endocytosis or nuclear transport following xray treatment of hela or head and neck cancer cells, despite extensive dna damage. Inhibition of p38 mapk increases xrcc1 recruitment to sites of dna damage. Therefore, p38 mapk is required for the synergistic induction of inos by.
Dominant negative taos block p38 activation by genotoxic stress. Jul 24, 2017 inhibition of p38 mapk increases xrcc1 recruitment to sites of dna damage. Nuclear localization of p38 mapk in response to dna damage. Activation of p38 mapk has been reported to be essential for survival of cells in response to stimuli that cause a type of dna damage. Among intracellular ros, which are able to induce dna damage, h 2 o 2 is known to provoke an appearance of both ssbs and dsbs that can trigger ddr. The role of the p38 mapk pathway in the g2 dna damage checkpoint of cancer cells has recently been called into question by the observation that transformed.
Mapk14 is one of the four p38 mapks which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. However, how dna damage leads to the activation of p53 is still poorly understood. Pdf the role of p38 mapk pathway in p53 compromised state. Agnps exposure activates p38 mitogenactivated protein kinase through nuclear factore2related factor2 and nuclear factorkappab signaling pathways, subsequently inducing dna damage, cell cycle arrest and apoptosis. Hyperproliferative signals generated by activated mekerk may cause hyperreplication of dna, generating dna damage that is known to activate p38 and induce senescence 9,10,33. These data demonstrate that mir34c is a critical regulator of the cmyc expression following dna damage acting downstream of p38 mapk mk2 and suggest that. During ddr, the mekerk pathway is regularly activated, which contributes to the appropriate activation of ddr checkpoints to inhibit cell division. Knockdown of tao kinases inhibits activation of p38 by dna damage to obtain additional evidence that taos are required for p38 activation by dna damage, we used sirna to examine p38 activation by uv, hu and ir in cells with reduced tao expression. Through the use of inactive and constitutively active mutants of mkk3 and 6 as well as the p38 inhibitor sb203580, numerous genes regulated by the p38 map kinase pathway have been identified. The selective nuclear accumulation of p38 mapk in response to dna damage could be a mechanism to facilitate the phosphorylation of p38 mapk nuclear targets for the induction of a g2m cell cycle checkpoint and dna repair. It is clear that the regulation of p38 mapk signaling is complex. Egf receptor egfr endocytosis is induced by stress in a manner dependent on the p38 mapk family.
Here we show that following etoposideinduced dna damage translation of cmyc is repressed by mir34c via a highly conserved targetsite within the 3. While chk1 is known to mediate g2 dna damage checkpoint control, p38 was also reported to have an essential function in this checkpoint control. Novel strategies for inhibition of the p38 mapk pathway. The role of p38 mapk pathway in p53 compromised state and. Exactly how cisplatin triggers stress kinase pathways is not yet known, nor are the sequential events between cddpinduced oxidative stress, dna damage, jnk p38 activation, and. Nuclear localization of p38mapk in response to dna damage. In most cases, cellular responses to dna damage or replication stress are initiated by the activation of sensor. Activation and signaling of the p38 map kinase pathway.
Pretreatment with sb202190, a specific inhibitor of p38 mapks, significantly reduced mechanical stressinduced p53 activation. Our previous findings indicated that p38 mapk may be involved in transducing signals leading to cell death. The kinase ataxia telangiectasia and rad3related protein atr, together with its downstream effector kinases, such as chk1, is one of the master regulators of the dna damage induced response ddr. Atrdependent activation of p38 map kinase is responsible for.
Figure 1 oncogenic rasinduced senescence is mediated by sequential activation of the rafmekerk and mkk36 p38 pathways. Hyunjeong eom and jinhee choi school of environmental engineering, college of urban science, university of seoul, 90 jeonnongdong. Research article open access p38 mitogenactivated protein. Agnps induce significant and selective toxicity to jurkat t cells via p38 mapk activation, dna damage, cell cycle arrest, and apoptosis. The selective nuclear accumulation of p38 mapk in response to dna damage could pose a mechanism to facilitate the phosphorylation of p38 mapk nuclear targets for the induction of a g2m cell cycle checkpoint and dna repair. Nuclear translocation of p38 mapk does not require its catalytic activity, but is induced by a conformational change of p38 mapk triggered by phosphorylation within the active site. Pbktopk promotes tumour cell proliferation through p38 mapk activity and regulation of the dna damage response. In addition to apoptosis, ika may be able to trigger a form of cell death that is independent of caspase activation. Ligand and stresses such as xrays, reportedly promote nuclear trafficking of endocytosed egfr for regulation of gene transcription and dna repair. Jojournalurnal tao kinases mediate activation of p38 in. Erk and p38 mapk activities determine sensitivity to pi3k. Effect of pbk knockdown on p38 activation after dna damage. P38 mitogenactivated protein kinases are a class of mitogenactivated protein kinases mapks that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy. Doramapimod birb 796 doramapimod birb 796 is a panp38 mapk inhibitor with ic50 of 38 nm, 65 nm, 200 nm and 520 nm for p38.
Generally, ddr is characterized by activation of ataxiatelangiectasia mutated kinase atm and formation of dna damage foci, containing. Interaction between ros dependent dna damage, mitochondria. Crosstalk between atm, p38mapk and shelterin complex. The intracellular localization of p38 mapk upon activation remains unclear, and may depend on the stimulus. Dna damage, and mediates death, cell differentiation and cell cycle checkpoints. Our results imply a direct impact of the p38map kinaseactivated protein kinase 2 mk2 kinase pathway on the cellular response to replicative. Thus, the activation of p38 mapk regardless of the upstream signaling pathway seems to be. Other mapk pathways activated by radiation include those downstream of death receptors and procaspases, and dna damage signals, including the jnk and p38 mapk pathways. Since a nuclear translocation of p38 mapk upon cell stimulation has not been previously reported, we examined the distribution of p38 mapk in response to other known activators which do not induce dna damage. However, in the resistant cells, p38 activity was significantly suppressed, as were markers of dna repair, suggesting that. To assess the role of p38 mapk pathway in nucleotide excision repair ner, the most versatile dna repair pathway, we determined the. Mechanical stressinduced dna damage and racp38mapk signal. Serinethreonine kinase which acts as an essential component of the map kinase signal transduction pathway. Mar 23, 2010 here we show that following etoposideinduced dna damage translation of cmyc is repressed by mir34c via a highly conserved targetsite within the 3.
Specifically, it has been shown that oncogenic rasinduced ros cause activation of dna damage responses. We show here that activation of p38 mapk by stimuli that induce dna double strand breaks dsbs, but not other stimuli. The molecular pathways triggered by anticancer drugs that lead to the activation of stress pathways are not well understood. Oncogenic ras initially activates the rafmekerk pathway. Damageinduced dna replication stalling relies on mapkactivated. Hydroxyurea exposure triggers tissuespecific activation of. Emerging roles of the p38 mapk and pi3kaktmtor pathways. Mir34 is induced by p38 mapk mk2 signalling following dna damage.
In addition to apoptosis, ika may be able to trigger a form of cell death that is independent of caspaseactivation dotted line. Jun 12, 2014 among intracellular ros, which are able to induce dna damage, h 2 o 2 is known to provoke an appearance of both ssbs and dsbs that can trigger ddr. Activation of different mapk might play an important role in the np toxicity outcomes. Tao kinases mediate activation of p38 in response to dna.
Many cellular stressors like heat shock, osmotic stress, and microtubule depolymerization induce cell cycle arrest via robust activation of p38 map kinase mapk. Tao kinases mediate activation of p38 in response to dna damage. Activation of p38 mitogenactivated protein kinase is. The p38 mapk signaling activation in colorectal cancer. Although our data do not delineate how p38 activity is suppressed in the resistant cells, our results and that of others suggest that acute pi3kmtor inhibition leads to dna damage and activation of dna repair pathways. Pbktopk promotes tumour cell proliferation through p38. Despite its role in the induction of cell cycle checkpoints in response to dsbs inducing stimuli, little is known about the intracellular distribution of p38 mapk following its activation by dsbs. Of note, the involvement of ros and dna damage in the sequential activation of the erk and p38 pathways may not be mutually exclusive, as ros is a known dna damaging. The mitogenactivated protein kinase mapk signaling pathway is known to be activated by uvr and herein we identify p38 mapk as a key modulator of these physiologic events. The p38 mapk pathway was shown to be activated in response to agents such as curcumin which induced apoptosis in cisplatinresistant ovarian cancer cells. This study was designed to investigate oxidative dna damage, the activation of atm, a reporter of dna damage, and redoxsensitive signal transduction through mitogenactivated protein kinases mapks by the monomer triethylene glycol dimethacrylate tegdma.