Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian cells treated with ultraviolet (UV) light provide one of the best-known experimental systems for depicting the biological consequences of DNA damage. UV irradiation induces the formation of DNA photoproducts, mainly cyclobutane pyrimidine dimers (CPDs) and (6-4) pyrimidine-pyrimidone photoproducts [(6-4)PPs], that drastically impairs DNA metabolism, culminating in the induction of cell death by apoptosis. While CPDs are the most important apoptosis-inducing lesions in DNA repair proficient cells, recent data indicates that (6-4)PPs also signals for apoptosis in DNA repair deficient cells. The toxic effects of these unrepaired DNA lesions are commonly associated with transcription blockage, but there is increasing evidence supporting a role for replication blockage as an apoptosis-inducing signal. This is supported by the observations that DNA double-strand breaks (DSBs) arise at the sites of stalled replication forks, that these DSBs are potent inducers of apoptosis and that inhibition of S phase progression diminishes the apoptotic response. Reactive oxygen species, generated after exposure of mammalian cells to longer UV wavelengths, may also induce apoptotic responses. In this regard, emphasis is given to the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxoG), but indirect induced lesions such as lipoperoxide DNA adducts also deserve attention. ATR is the main established sensor molecule for UV-induced DNA damage. However, there is evidence that ATM as well as the MAPK pathway also play a role in the UV response by activating either the death receptor or the mitochondrial damage pathway. Adding more complexity to the subject, cells under stress suffer other types of processes that may result in cell death. Autophagy is one of these processes, with extensive cross-talks with apoptosis. No matter the mechanisms, cell death avoids cells to perpetuate mutations induced by genotoxic lesions. The understanding of such death responses may provide the means for the development of strategies for the prevention and treatment of cancer.
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PMID:How DNA lesions are turned into powerful killing structures: insights from UV-induced apoptosis. 1884 70

While it has been reported that genistein induces differentiation in multiple tumour cell models, the signalling and regulation of isoflavone-provoked differentiation are poorly known. We here demonstrate that genistein causes G(2)/M cycle arrest and expression of differentiation markers in human acute myeloid leukaemia cells (HL60, NB4), and cooperates with all-trans retinoic acid (ATRA) in inducing differentiation, while ATRA attenuates the isoflavone-provoked toxicity. Genistein rapidly stimulates Raf-1, MEK1/2 and ERK1/2 phosphorylation/activation, but does not stimulate and instead causes a late decrease in Akt phosphorylation/activation which is attenuated by ATRA. Both differentiation and G(2)/M arrest are attenuated by MEK/ERK inhibitors (PD98059, U0126) and ERK1-/ERK2-directed small interfering RNAs (siRNAs), and by the PI3K inhibitor LY294002, but not by the p38-MAPK inhibitor SB203580. Genistein stimulates p21(waf1/cip1) and cyclin B1 expression, phosphorylation/activation of ATM and Chk2 kinases, and Tyr15-phosphorylation/inactivation of Cdc2 (Cdk1) kinase, and these effects are attenuated by MEK/ERK inhibitors, while LY294002 also attenuates ERK and ATM phosphorylation. Caffeine abrogates the genistein-provoked G(2)/M blockade and alterations in cell cycle regulatory proteins, and also suppresses differentiation. Finally, genistein causes reactive oxygen species (ROS) over-accumulation, but the antioxidant N-acetyl-L-cysteine fails to prevent ERK activation, G(2)/M arrest, and differentiation induction. By contrast, N-acetyl-L-cysteine and p38-MAPK inhibitor attenuate the apoptosis-sensitizing (pro-apoptotic) action of genistein when combined with the antileukaemic agent arsenic trioxide. In summary, genistein-induced differentiation in acute myeloid leukaemia cells is a ROS-independent, Raf-1/MEK/ERK-mediated and PI3K-dependent response, which is coupled and co-regulated with G(2)/M arrest, but uncoupled to the pro-apoptotic action of the drug.
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PMID:Regulation of genistein-induced differentiation in human acute myeloid leukaemia cells (HL60, NB4) Protein kinase modulation and reactive oxygen species generation. 1903 32

The impact of DNA damage-induced replication blockage for early activation of stress kinases [stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)] is largely unknown. Here, we show that induction of dual phosphorylation of SAPK/JNK by the DNA polymerase inhibitor aphidicolin was not ameliorated by additional exposure to ultraviolet (UV) light, indicating that overlapping mechanisms participate in signaling to SAPK/JNK triggered by both agents. UV-induced DNA replication blockage, cyclobutane pyrimidine dimer formation and DNA strand break induction coincided with SAPK/JNK phosphorylation at early (< or =30 min) but not late (> or =2 h) time points after exposure. Genotoxin-stimulated SAPK/JNK activation was attenuated in nonproliferating cells, indicating that S phase-dependent mechanisms are involved in signaling to SAPK/JNK. Correspondingly, UV-induced phosphorylation of SAPK/JNK was higher in S-phase cells as compared with G(1)-phase cells. Activation of SAPK/JNK by genotoxins was below detection limit in nonproliferating human peripheral blood lymphocytes, whereas peripheral blood lymphocytes stimulated to proliferation displayed clear SAPK/JNK activation. UV-induced phosphorylation of SAPK/JNK was attenuated in XPC-defective cells, ameliorated in BRCA2 mutated cells and not changed in cells lacking ATM, DNA-PK, CSB, XPA, p53, ERCC1 or PARP as compared with the corresponding wild types. Based on these data, we suggest that DNA replication blockage caused by genotoxin-induced DNA damage contributes to early activation of SAPK/JNK.
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PMID:DNA replication arrest in response to genotoxic stress provokes early activation of stress-activated protein kinases (SAPK/JNK). 1910 74

The development of strategies for the protection of oral tissues against the adverse effects of resin monomers is primarily based on the elucidation of underlying molecular mechanisms. The generation of reactive oxygen species beyond the capacity of a balanced redox regulation in cells is probably a cause of cell damage. This study was designed to investigate oxidative DNA damage, the activation of ATM, a reporter of DNA damage, and redox-sensitive signal transduction through mitogen-activated protein kinases (MAPKs) by the monomer triethylene glycol dimethacrylate (TEGDMA). TEGDMA concentrations as high as 3-5 mM decreased THP-1 cell viability after a 24h and 48h exposure, and levels of 8-oxoguanine (8-oxoG) increased about 3- to 5-fold. The cells were partially protected from toxicity in the presence of N-acetylcysteine (NAC). TEGDMA also induced a delay in the cell cycle. The number of THP-1 cells increased about 2-fold in G1 phase and 5-fold in G2 phase in cultures treated with 3-5 mM TEGDMA. ATM was activated in THP-1 cells by TEGDMA. Likewise, the amounts of phospho-p38 were increased about 3-fold by 3 mM TEGDMA compared to untreated controls after a 24h and 48h exposure period, and phospho-ERK1/2 was induced in a very similar way. The activation of both MAPKs was inhibited by NAC. Our findings suggest that the activation of various signal transduction pathways is related to oxidative stress caused by a resin monomer. Signaling through ATM indicates oxidative DNA damage and the activation of MAPK pathways indicates oxidative stress-induced regulation of cell survival and apoptosis.
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PMID:TEGDMA-induced oxidative DNA damage and activation of ATM and MAP kinases. 1913 96

The gene that encodes the ATM protein kinase is mutated in ataxia-telangiectasia (A-T). One of the prominent features of A-T is progressive neurodegeneration. We have previously reported that primary astrocytes isolated from Atm(-/-) mice grow slowly and die earlier than control cells in culture. However, the mechanisms for this remain unclear. We show here that intrinsic elevated intracellular levels of reactive oxygen species (ROS) are associated with the senescence-like growth defect of Atm(-/-) astrocytes. This condition is accompanied by constitutively higher levels of ERK1/2 phosphorylation and p16(Ink4a) in Atm(-/-) astrocytes. We also observe that ROS-induced up-regulation of p16(Ink4a) occurs correlatively with ERK1/2-dependent down-regulation and subsequent dissociation from chromatin of Bmi-1. Furthermore, both mitogen-activated protein kinase (MAPK)/ERK inhibitor PD98059 and antioxidant N-acetyl-l-cysteine restored normal proliferation of Atm(-/-) astrocytes. These results suggest that ATM is required for normal astrocyte growth through its ability to stabilize intracellular redox status and that the inability to control ROS is the molecular basis of limited cell growth of Atm(-/-) astrocytes. This defect may be mediated by a mechanism involving ERK1/2 activation and Bmi-1 derepression of p16(Ink4a). These data identify new potential targets for therapeutic intervention in A-T neurodegeneration.
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PMID:Oxidative stress is linked to ERK1/2-p16 signaling-mediated growth defect in ATM-deficient astrocytes. 1932 50

Elucidating the molecular mechanism of the low-dose radiation (LDR)-mediated radioadaptive response is crucial for inventing potential therapeutic approaches to improving normal tissue protection in radiation therapy. ATM, a DNA-damage sensor, is known to activate the stress-sensitive transcription factor NF-kappaB upon exposure to ionizing radiation. This study provides evidence of the cooperative functions of ATM, ERK, and NF-kappaB in inducing a survival advantage through a radioadaptive response as a result of LDR treatment (10 cGy X-rays). By using p53-inhibited human skin keratinocytes, we show that phosphorylation of ATM, MEK, and ERK (but not JNK or p38) is enhanced along with a twofold increase in NF-kappaB luciferase activity at 24 h post-LDR. However, NF-kappaB reporter gene transactivation without a significant enhancement of p65 or p50 protein level suggests that NF-kappaB is activated as a rapid protein response via ATM without involving the transcriptional activation of NF-kappaB subunit genes. A direct interaction between ATM and NF-kappaB p65 is detected in the resting cells and this interaction is significantly increased with LDR treatment. Inhibition of ATM with caffeine, KU-55933, or siRNA or inhibition of the MEK/ERK pathway can block the LDR-induced NF-kappaB activation and eliminate the LDR-induced survival advantage. Altogether, these results suggest a p53-independent prosurvival network involving the coactivation of the ATM, MEK/ERK, and NF-kappaB pathways in LDR-treated human skin keratinocytes, which is absent from mutant IkappaB cells (HK18/mIkappaB), which fail to express NF-kappaB activity.
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PMID:Coactivation of ATM/ERK/NF-kappaB in the low-dose radiation-induced radioadaptive response in human skin keratinocytes. 1932 81

In response to various environmental stresses, the stress-responsive MAPKs p38 and JNK are activated and phosphorylate ATF2 and c-Jun transcription factors, thereby affecting cell-fate decision. Targeted gene disruption studies have established that JNK-c-Jun signaling plays a vital role in stress-induced apoptosis. The oncogenic phosphatase Wip1 acts as an important regulator in DNA damage pathway by dephosphorylating a spectrum of proteins including p53, p38, Chk1, Chk2, and ATM. In this study we show that Wip1 negatively regulates the activation of MKK4-JNK-c-Jun signaling during stress-induced apoptosis. The loss of Wip1 function sensitizes mouse embryonic fibroblasts to stress-induced apoptosis via the activation of both p38-ATF2 and JNK-c-Jun signaling. Here we reveal that Wip1 has dual roles in alternatively regulating stress- and DNA damage-induced apoptosis through p38/JNK MAPKs and p38/p53-dependent pathways, respectively. Our results point to Wip1 as a general regulator of apoptosis, which further supports its role in tumorigenesis.
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PMID:Loss of Wip1 sensitizes cells to stress- and DNA damage-induced apoptosis. 1939 78

Hypoxia-inducible factor-1 (HIF-1) plays a central role in tumor progression by regulating genes involved in proliferation, glycolysis, angiogenesis, and metastasis. To improve our understanding of HIF-1 regulation by kinome, we screened a kinase-specific small interference RNA library using a hypoxia-response element (HRE) luciferase reporter assay under hypoxic conditions. This screen determined that depletion of cellular SMG-1 kinase most significantly modified cellular HIF-1 activity in hypoxia. SMG-1 is the newest and least studied member of the phosphoinositide 3-kinase-related kinase family, which consists of ATM, ATR, DNA-PKcs, mTOR, and SMG-1. We individually depleted members of the phosphoinositide 3-kinase-related kinase family, and only SMG-1 deficiency significantly augmented HIF-1 activity in hypoxia. We subsequently discovered that SMG-1 kinase activity was activated by hypoxia, and depletion of SMG-1 up-regulated MAPK activity under low oxygen. Suppressing cellular MAPK by silencing ERK1/2 or by treatment with U0126, a MAPK inhibitor, partially blocked the escalation of HIF-1 activity resulting from SMG-1 deficiency in hypoxic cells. Increased expression of SMG-1 but not kinase-dead SMG-1 effectively inhibited the activity of HIF-1alpha. In addition, cellular SMG-1 deficiency increased secretion of the HIF-1alpha-regulated angiogenic factor, vascular epidermal growth factor, and survival factor, carbonic anhydrase IX (CA9), as well as promoted the hypoxic cell motility. Taken together, we discovered that SMG-1 negatively regulated HIF-1alpha activity in hypoxia, in part through blocking MAPK activation.
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PMID:Kinome siRNA screen identifies SMG-1 as a negative regulator of hypoxia-inducible factor-1alpha in hypoxia. 1940 46

Nucleus pulposus intervertebral disc cells experience a broad range of physicochemical stimuli in their native environment including osmotic fluctuations. Here we show that hyperosmotic treatment reduced nucleus pulposus cells' proliferation by activating the G2 and G1 cell cycle checkpoints. p38 MAPK was found to participate in the manifestation of the G2 arrest under conditions of increased osmolality, since inhibition of its activity by SB203580 released the cells from G2 phase into mitosis. High osmolality resulted in the ATM-mediated phosphorylation of p53 on Ser15, the up-regulation of p21(WAF1) and the hypophosphorylation of the retinoblastoma protein in accordance to the observed G1 arrest. siRNA knocking down of p53 inhibited the expression of p21(WAF1) while maintaining the hyperphosphorylated form of the retinoblastoma protein and thus abrogated the G1 arrest observed under hyperosmotic conditions. Comet assay revealed that high osmolality provoked DNA damage to nucleus pulposus cells. Several previous reports have shown that renal cells become unable to sense and repair DNA damage under conditions of increased osmolality. On the contrary, nucleus pulposus cells residing within a hyperosmotic environment clearly preserved their ability to sense newly introduced DNA damage, as confirmed by the reactivation of p53 by ionizing radiation, retained the MRN complex in the nucleus and phosphorylated H2A.X on Ser139. H2A.X phosphorylation was attenuated in cells persistently experiencing hyperosmotic stress which, combined with the concurrent reduction in comet tails' length, indicated an active DNA repair machinery. Even more, when the DNA repair efficiency of nucleus pulposus cells was directly measured by a host cell reactivation of luciferase activity assay, it was found to be significantly increased under hyperosmotic pressure. Finally, p53 depletion of nucleus pulposus cells by siRNA enhanced and prolonged H2A.X phosphorylation, attributing to p53 a regulatory role in the DNA repair pathway induced by increased osmolality.
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PMID:High osmolality activates the G1 and G2 cell cycle checkpoints and affects the DNA integrity of nucleus pulposus intervertebral disc cells triggering an enhanced DNA repair response. 1953 2

Ataxia-telangiectasia (A-T) is a genetic disorder caused by a mutation of the Atm gene, which controls DNA repair, cell cycling, and redox homeostasis. Even though oxidative stress has been implicated in the neurological anomalies in A-T, the effects of ATM loss on neural stem cell (NSC) survival has remained elusive. In this study, we investigated the effects of oxidative stress on NSC proliferation in an animal model for A-T neurodegeneration. We found that cultured subventricular zone neurosphere cells from Atm(-/-) mice show impaired proliferation, as well as intrinsic elevation of reactive oxygen species (ROS) levels, compared with those from Atm(+/+) mice. We also show that increasing the levels of ROS by H(2)O(2) treatment significantly reduces Atm(+/+) neurosphere formation and proliferation. In Atm(-/-) neurosphere cells, the Akt and Erk1/2 pathways are disrupted, together with enhanced activity of the p38 mitogen-activated protein kinase (MAPK). Treatment of these cells with the antioxidant N-acetyl-L-cysteine (NAC) or with a p38 MAPK inhibitor restores normal proliferation and reduced expression of p21(cip1) and p27(kip1) in the Atm(-/-) NSCs. These observations indicate that ATM plays a crucial role in NSC proliferation, by activating Akt and Erk1/2 pathways and by suppressing ROS-p38 MAPK signaling. Together, our results suggest that p38 MAPK signaling acts as a negative regulator of NSC proliferation in response to oxidative stress. These findings suggest a potential mechanism for neuronal cell loss as a result of oxidative stress in NSCs in progressive neurodegenerative diseases such as A-T.
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PMID:Loss of ATM impairs proliferation of neural stem cells through oxidative stress-mediated p38 MAPK signaling. 1954 30


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