Jun nterminal kinase jnk and p38 mitogenactivated protein kinase mapk signalling pathways are involved in a vast array of cellular events and are often altered in human cancers. Atrdependent activation of p38 map kinase is responsible for. This, in turn, leads to increase the expressions and protein interactions of p53 and foxo3a, followed by the induction of cell cycle inhibitor p21 cip1waf1. Regulation of atmdependent dna damage responses in breast. The genetic basis of signaling cascade deregulation relies on somatic mutations in components of these pathways, as reported in a largescale screening study on the status of protein kinases in tumors. The levels of phosphorylated p38 mapk were significantly reduced in clockdeficient cells, indicating that the circadian clock plays an important role in activation of this pathway. Kinase regulates the dna damage response and drives. The tumor suppressor p53 plays a central role in sensing damaged dna and orchestrating the consequent cellular responses. Stressspecific p38 mapk activation is sufficient to drive. Mitogenactivated protein kinase p38 and retinoblastoma. A role for the p38 mitogenactivated protein kinase. Agnps exposure activates p38 mitogenactivated protein kinase through nuclear factore2related factor2 and nuclear factorkappab signaling pathways, subsequently inducing dna. However, in the resistant cells, p38 activity was significantly suppressed, as were markers of dna repair, suggesting that these cells have resolved the dna damage stress leading to p38 activation.
New model for a novel role of p38 mapk in the dna damage response in cancer cells. Mar 29, 2007 here we show that the tao kinases mediate the activation of p38 in response to various genotoxic stimuli. Inhibition of p38 mapk increases xrcc1 recruitment to sites of dna damage. Activation of p38 mapk is a critical requisite for the therapeutics activity of the antitumor agent cisplatin. Tao kinases mediate activation of p38 in response to dna damage. During ddr, the mekerk pathway is regularly activated, which contributes to the appropriate activation of ddr checkpoints to inhibit cell division. 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. Atr, a major sensor kinase for checkpoint or dna damage responses. Dec 11, 2006 taken together, these data indicate that pbk contributes to the appropriate activation of the dna damage response, including p38 activation and h2ax phosphorylation, and that the defects in dna. The p38 mitogenactivated protein kinase augments nucleotide. The intracellular localization of p38 mapk upon activation remains unclear, and may depend on the stimulus. Specifically, it has been shown that oncogenic rasinduced ros cause activation of.
Damageinduced dna replication stalling relies on mapkactivated. It is clear that the regulation of p38 mapk signaling is complex. 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. The mapk pathway signals telomerase modulation in response to. However, in the resistant cells, p38 activity was significantly suppressed, as were markers of dna repair, suggesting that. Transcriptional activation of mir320a by atf2, elk1 and. Tao kinases are activated acutely by ionizing radiation, ultraviolet radiation, and hydroxyurea. We show that, in the absence of p53, cells depend on a third cellcycle checkpoint pathway involving p38mapkmk2 for cellcycle arrest and survival after dna damage.
This is mediated by mapk activation but independent from production of reactive oxygen species ros. The change in phosphorylation status of endogenous xrcc1 after kinase inhibitor treatment prompted us to investigate the. Ikarugamycin induces dna damage, intracellular calcium. Rasmapk signaling functions in oxidative stress, dna damage. 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. Dna damageinduced chk2 activation compromises germline stem cell selfrenewal and. The mechanism by which dna dsbs activate p38 mapk is not completely clear. Mapk signaling mediates sinomenine hydrochlorideinduced. Uvinduced g2 checkpoint depends on p38 mapk and minimal. High level of ercc1 expression in cancers is associated with resistance to dna damagebased chemotherapy. 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.
Dna damage dependent activation of checkpoint kinase1 and. 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 dnadamaging agent. Our results suggest that in human nsclc cells, ercc1 is induced by etoposide through the p38 mapk pathway, and this phenomenon is required for nsclc survival and resistant dna damage. Pivotal role for ros activation of p38 mapk in the control of differentiation and tumor. Tao kinases mediate activation of p38 in response to dna. In this study, the effects of p38 mitogenactivated protein kinase mapk signal on the ercc1 expression induced by etoposide in nonsmall cell lung cancer nsclc cell lines was investigated. Ros contributes to shinduced breast cancer dna damage.
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. However, how dna damage leads to the activation of p53 is still poorly understood. Rnai of taos diminishes not only p38 activation but also impairs the dna damage. Signal integration by jnk and p38 mapk pathways in cancer. 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. Pbktopk promotes tumour cell proliferation through p38. While chk1 is known to mediate g2 dna damage checkpoint control, p38 was also reported to have an essential function in this checkpoint control. Elk1 is a component of the ternary complex that binds the serum response element sre in response to serum growth factors. However, the ddr is not solely dependent upon p53, since p53deficient cells can still respond to and repair dna damage.
Thus, the role of net1 in controlling ir responses and cell survival is controversial. Moreover, mk2 represents a determinant of cancer cell sensitivity toward. Role of p38 mapk signaling pathway and sigma 1 receptor on induction of apoptosis in response to ad. The tumor suppressor protein, p53 is a major downstream effector of these. High expression of prkdc promotes breast cancer cell. One mechanism by which cmyc induces dna damage is through binding directly to components of the prereplicative complex thereby promoting dna synthesis, resulting in replicationassociated dna damage and checkpoint activation due to inappropriate origin firing. 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. Mar 23, 2010 inappropriate expression of the protooncogene cmyc is known to cause dna damage. In response to dna damage, the chk1mediated g 2 dna damage. Doramapimod birb 796 doramapimod birb 796 is a pan p38 mapk inhibitor with ic50 of 38 nm, 65 nm, 200 nm and 520 nm for p38. In the absence of p53 the p38 mapk pathway is essential for survival in response to chemotherapeutic drugs that cause dna damage, due to loss of mk2mediated sphase and or g2m arrest. Recently, attention has focused on the bicyclic pyridinyl imidazole class of compounds such as sb 203580 and sb 202190, which are potent inhibitors of tnf.
Dna damaging drugs are able to induce irreversible cell growth arrest and senescence accompanied by upregulation of p53, p21 and p16ink4a protein. Thus, the discovery of novel p53inhibitory targets may signi. The mitogenactivated protein kinase mapk cascade is a critical pathway for human cancer cell survival, dissemination, and resistance to drug therapy. Inhibition of p38 mapk totally abolished the dna damage induced by omeo figure 9b. Pdf the role of p38 mapk pathway in p53 compromised. The anticancer activity of many chemotherapy drugs relies on the induction of dna damage and followed cellular response triggered by p53. To test whether dna damage is a cause or a consequence of p38 mapk activation, the level of. In addition, dna damage is a partly common circumstance in cell life and may result in mutation, cancer, and even cell death. Abl as a major determinant of p38 mapk activation, especially in response. Astaxanthin enhances erlotinibinduced cytotoxicity by p38. Atf2 is regulated by p38 mapk jnk in response to stress and plays a role in the dna damage response and atm phosphorylates atf2 on ser490 and ser498 following exposure to ir 35,36.
The activation of p38 map kinase in the cdc7depleted cells was shown. In addition to apoptosis, ika may be able to trigger a form of cell death that is independent of caspaseactivation dotted line. Mitogenactivated protein kinase 14, also called p38. Mapkmediated induction and interaction of foxo3a and. The p38 mapk is a family of serinethreonine protein kinases that play. Origanum majorana essential oil triggers p38 mapkmediated. 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.
Inhibition of p38 mapkdependent excision repair cross. However, others have shown that net1 activation contributes to rhobmediated cell death after ir. Apr 26, 2014 in this report, we show that bbr inhibits growth and induces apoptosis of lung adenocarcinoma cells through activation of p38 mitogen activated protein kinase alpha p38. In this sense, a growing body of evidences supports the role of c. The role of p38 mapk pathway in p53 compromised state and. Besides the p53p21 and p16rb pathways, other pathways, such as the mitogenactivated protein kinase p38 p38 mapk pathway, are also involved in dna damaging druginduced senescence. Ligand and stresses such as xrays, reportedly promote nuclear trafficking of endocytosed egfr for regulation of gene transcription and dna repair. Studies demonstrated that the map kinases extracellular signal.
Abl activates p38 mapk independently of its tyrosine. A number of drugs used for cancer chemotherapy induce damage dna, resulting in cell death, and p38. Agnps induce significant and selective toxicity to jurkat t cells via p38 mapk activation, dna damage, cell cycle arrest, and apoptosis. Moreover, incubation of caco2 and sw620 human colon cancer cell lines with three different p38 mapk chemical inhibitors resulted in enhanced apoptosis figure 8e, which correlated with increased levels of phosphorylated jnk figure 8e, as observed on p38. We have previously reported that dna damage activates net1 to control rhoa and p38 mapk mediated cell survival pathway in response to ionizing radiation ir. High expression of prkdc promotes breast cancer cell growth. The activation of these kinases is a critical determinant of the dna damage response. Hydroxyurea exposure triggers tissuespecific activation. Many studies have demonstrated that apoptosis induction plays the most vital role in the cancer treatment by chemo. While chk1 is known to mediate g 2 dna damage checkpoint control, p38 was also reported to have an essential function in this checkpoint control. The deficiency of xpc induces the accumulation of the endogenous dna damage, and then activates the erksnailecadherin pathway. 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.
Role of p38 map kinase signal transduction in solid tumors. 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. In response to dna damage, eukaryotic cells activate atmchk2 andor atrchk1 to arrest the cell cycle and initiate dna repair. The molecular pathways triggered by anticancer drugs that lead to the activation of stress pathways are not well understood. Dna damage activates a complex signalling network that functions to. Our results imply a direct impact of the p38map kinaseactivated protein.
Egf receptor egfr endocytosis is induced by stress in a manner dependent on the p38 mapk family. Interestingly, the tumor suppressor protein p53, which enhances. In this report, we show that bbr inhibits growth and induces apoptosis of lung adenocarcinoma cells through activation of p38 mitogen activated protein kinase alpha p38. Emerging roles of the p38 mapk and pi3kaktmtor pathways. However, how dna damage leads to the activation of p53 is still poorly. Chk1 inhibition activates p53 through p38 mapk in tetraploid cancer. 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. The specific pathways connecting dna damage to p38 mapk activation may vary. H2ax was measured in cells treated with the p38 inhibitors prior to incubation with omeo. Pdf p38 mitogenactivated protein kinase promotes cell.
By contrast, p38 mapk is phosphorylated in g2 phase cells after uv damage. Dna damage elicits the activation of cell cycle checkpoint, dna repair, and cell survival signaling pathways. Hydroxyurea exposure triggers tissuespecific activation of. Within one hour, mtbitc induced dna damage in cancer cells correlating to a transient increase in htert mrna expression which then turned into telomerase suppression, evident at mrna as well as enzyme activity level. Agr2 oncoprotein inhibits p38 mapk and p53 activation through. However, recent braf inhibitor trials in cancer patients carrying brafmutated. 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 apoptosis. Erk and p38 mapk activation in a549 lung carcinoma cells and wi38 lung fibroblast cells was analyzed by immunoblotting after treatment with adenovirus figure 7bd. In response to dna damage stimuli that induce dsbs ionizing radiation, uv, chemotherapeutic drugs activation of p38 mapk can also lead to the induction of a g2m cell cycle checkpoint through p53dependent and independent mechanisms 1015. Sustained activation of jnkp38 mapk pathways in response to. Mal c elicits atmatr mediated p38 mapk activation in response to dna damage.
This suggested a rapid activation of dna damage response pathway in cancer cells by mal c treatment. Some anticancer drugs induce apoptosis in human cancer cells in association with the p38 mapk activation. 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. Taken together, these data indicate that pbk contributes to the appropriate activation of the dna damage response, including p38 activation and h2ax phosphorylation, and that the defects in dna.
Dna damage can obstruct replication forks, resulting in replicative stress. Rasmapk signaling functions in oxidative stress, dna. Uncontrolled proliferation is a result of altered signaling mechanisms and a hallmark of cancer. One of the main subgroups, the p38 map kinases, has been implicated in a wide range of complex biologic processes, such as cell proliferation, cell differentiation, cell death, cell migration, and invasion. Here we show that following etoposideinduced dna damage translation of cmyc is repressed by mir34c via a highly conserved targetsite within the 3. Activation of p38 mapk was observed in response to adeif5a1 and adeif5a1 k50a infection in both a549 cells and wi38 cells. Pbktopk promotes tumour cell proliferation through p38 mapk. 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 activity with vx745 led to celltypespecific period changes in the molecular clock. Dna damage induces the nuclear translocation of p38 mapk. Mk2 depletion in p53deficient cells, but not in p53 wildtype cells, caused abrogation.
Thimerosalinduced apoptosis in human scm1 gastric cancer cells. Previous studies suggested that activation of p38 mapk signaling and erk mapk signaling pathways by dna damage stimuli e. Thimerosalinduced apoptosis in human scm1 gastric 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. Role of p38 mapk signaling pathway and sigma 1 receptor on. 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. 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. Prostate cancer patients with dna damage repair mutations may respond to platinum chemo. Interestingly, despite the lack of an obvious activation of the atrchk1 pathway, only the combined inhibition of the atr and p38 dependent pathways results in a complete abrogation of the uvinduced g2m arrest. Mitogenactivated protein kinases mapks mediate a wide variety of cellular behaviors in response to extracellular stimuli.
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