Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When A549 cells were exposed to sodium metavanadate (NaVO(3)), the pentavalent species of vanadium (vanadate), phosphorylation of p53 protein at Ser15 was found in a time (8-48 h)- and dose (10-200 microM)-dependent manner. After the incubation with 50 or 100 microM NaVO(3) for 48 h, accumulation of p53 protein was accompanied with Ser15 phosphorylation. Among serines in p53 protein immunoprecipitated from A549 cells treated with 100 microM NaVO(3) for 48 h, only Ser15 was markedly phosphorylated. Treatment with other vanadate compounds, sodium orthovanadate (Na(3)VO(4)) and ammonium metavanadate (NH(4)VO(3)), also induced Ser15 phosphorylation and accumulation of p53 protein. While phosphorylation of extracellular signal-regulated protein kinase (ERK) was found in cells treated with NaVO(3), treatment with U0126 did not suppress Ser15 phosphorylation. On the other hand, treatment with wortmannin or caffeine, the inhibitors to phosphatidylinositol 3-kinase related kinases (PIKKs), suppressed both NaVO(3)-induced Ser15 phosphorylation and accumulation of p53 protein. The silencing of ataxia telangiectasia mutated (ATM) expression using short-interference RNA resulted in the marked suppression of Ser15 phosphorylation in A549 cells exposed to NaVO(3). However, treatment with antioxidants such as catalase and N-acetylcysteine did not suppress NaVO(3)-induced Ser15 phosphorylation. Transcriptional activation of p53 and DNA fragmentation in A549 cells treated with NaVO(3) were suppressed only slightly by S15A mutation, suggesting that Ser15 phosphorylation is not essential for these responses. The present results showed that vanadate induces the phosphorylation of p53 at Ser15 depending on ATM, one of the members of PIKK family, in this human pulmonary epithelial cell line.
...
PMID:Phosphorylation of p53 at serine 15 in A549 pulmonary epithelial cells exposed to vanadate: involvement of ATM pathway. 1729 32

Following DNA damage, cells undergo G2/M cell cycle arrest, allowing time for DNA repair. G2/M checkpoint activation involves activation of Wee1 and Chk1 kinases and inhibition of Cdc25A and Cdc25C phosphatases, which results in inhibition of Cdc2 kinase. Results presented in this report indicate that gamma-irradiation (IR) exposure of MCF-7 cells resulted in extracellular signal regulated protein kinase 1 and 2 (ERK1/2) activation and induction of G2/M arrest. Furthermore, inhibition of ERK1/2 signaling resulted in >or=85% attenuation in IR-induced G2/M arrest and concomitant diminution of IR-induced activation of ataxia telangiectasia mutated- and rad3-related (ATR), Chk1 and Wee1 kinases as well as phosphorylation of Cdc25A-Thr506, Cdc25C-Ser216 and Cdc2-Tyr15. Moreover, incubation of cells with caffeine, which inhibits ataxia telangiectasia mutated (ATM)/ATR, or transfection of cells with short interfering RNA targeting ATR abrogated IR-induced Chk1 phosphorylation and G2/M arrest but had no effect on IR-induced ERK1/2 activation. In contrast, inhibition of ERK1/2 signaling resulted in marked attenuation in IR-induced ATR activity with little, if any, effect on IR-induced ATM activation. These results implicate IR-induced ERK1/2 activation as an important regulator of G2/M checkpoint response to IR in MCF-7 cells.
...
PMID:Irradiation-induced G2/M checkpoint response requires ERK1/2 activation. 1729 54

Phosphorylation of p53 at Ser(46) is important to activate the apoptotic program. The protein kinase that phosphorylates p53 Ser(46) in response to DNA double-strand breaks is currently unknown. The identification of this kinase is of particular interest because it may contribute to the outcome of cancer therapy. Here, we report that ionizing radiation (IR) provokes homeodomain-interacting protein kinase 2 (HIPK2) accumulation, activation, and complex formation with p53. IR-induced HIPK2 up-regulation strictly correlates with p53 Ser(46) phosphorylation. Down-regulation of HIPK2 by RNA interference specifically inhibits IR-induced phosphorylation of p53 at Ser(46). Moreover, we show that HIPK2 activation after IR is regulated by the DNA damage checkpoint kinase ataxia telangiectasia mutated (ATM). Cells from ataxia telangiectasia patients show defects in HIPK2 accumulation. Concordantly, IR-induced HIPK2 accumulation is blocked by pharmacologic inhibition of ATM. Furthermore, ATM down-regulation by RNA interference inhibited IR-induced HIPK2 accumulation, whereas checkpoint kinase 2 deficiency showed no effect. Taken together, our findings indicate that HIPK2 is the IR-activated p53 Ser(46) kinase and is regulated by ATM.
...
PMID:Homeodomain-interacting protein kinase 2 is the ionizing radiation-activated p53 serine 46 kinase and is regulated by ATM. 1733 58

Poly(ADP-ribosyl)ation is a post-translational modification that is instantly stimulated by DNA strand breaks creating a unique signal for the modulation of protein functions in DNA repair and cell cycle checkpoint pathways. Here we report that lack of poly(ADP-ribose) synthesis leads to a compromised response to DNA damage. Deficiency in poly(ADP-ribosyl)ation metabolism induces profound cellular sensitivity to DNA-damaging agents, particularly in cells deficient for the protein kinase ataxia telangiectasia mutated (ATM). At the biochemical level, we examined the significance of poly(ADP-ribose) synthesis on the regulation of early DNA damage-induced signaling cascade initiated by ATM. Using potent PARP inhibitors and PARP-1 knock-out cells, we demonstrate a functional interplay between ATM and poly(ADP-ribose) that is important for the phosphorylation of p53, SMC1, and H2AX. For the first time, we demonstrate a functional and physical interaction between the major DSB signaling kinase, ATM and poly(ADP-ribosyl)ation by PARP-1, a key enzyme of chromatin remodeling. This study suggests that poly(ADP-ribose) might serve as a DNA damage sensory molecule that is critical for early DNA damage signaling.
...
PMID:Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. 1742 92

The diverse responses of human cells to various forms of DNA damage are controlled by a complex network of signaling proteins. There has been considerable interest in the components of this signaling apparatus as potential targets for new forms of anticancer therapy. In this report, we examine the contributions of an upstream signaling molecule, the ataxia telangiectasia mutated- and Rad3-related (ATR) protein kinase, to the resistance of cancer cells to DNA-damaging agents that are commonly used as anticancer therapeutics. Loss of ATR function in knock-in cancer cells strikingly enhanced the effects of several of the most commonly used therapeutic compounds, impeding the progression of the cell cycle and reducing long-term cancer cell survival. Loss of ATR function potentiated the toxicity of alkylating agents most strikingly, antimetabolites moderately, and double-strand break-inducing agents to a lesser extent. These results suggest that specific inhibition of ATR activity will be a valid strategy to increase the effectiveness of currently used modes of therapy.
...
PMID:Loss of ataxia telangiectasia mutated- and Rad3-related function potentiates the effects of chemotherapeutic drugs on cancer cell survival. 1743 Nov 19

Checkpoint kinase 2 (Chk2), a DNA damage-activated protein kinase, is phosphorylated at Thr-68 by ataxia telangiectasia mutated leading to its activation by phosphorylation at several additional sites. Using mass spectrometry we identified a new Chk2 phosphorylation site at Ser-456. We show that phosphorylation of Ser-456 plays a role in the regulation of Chk2 stability particularly after DNA damage. Mutation of Ser-456 to alanine results in hyperubiquitination of Chk2 and dramatically reduced Chk2 stability. Furthermore, cells expressing S456A Chk2 show a reduction in the apoptotic response to DNA damage. These findings suggest a mechanism for stabilization of Chk2 in response to DNA damage via phosphorylation at Ser-456 and proteasome-dependent turnover of Chk2 protein via dephosphorylation of the same residue.
...
PMID:Stability of checkpoint kinase 2 is regulated via phosphorylation at serine 456. 1771 38

Chromatin condensation and degradation of DNA into internucleosomal DNA fragments are key hallmarks of apoptosis. The phosphorylation of protein kinase ataxia telangiectasia mutated (ATM) and histone H2A.X was recently shown to occur concurrently with apoptotic DNA fragmentation. We have used immunofluorescence microscopy, Western blot analysis and alkali comet assays to show that phosphorylation of ATM in NIH3T3 fibroblasts occurs prior to apoptotic DNA fragmentation, nuclease degradation and phosphorylation of histone H2A.X in cells treated with low levels of either staurosporine (STS) or tumor necrosis factor-alpha mixed with cycloheximide (TNF-alpha/CHX). In extension to previous findings, ATM phosphorylation was associated with chromatin decondensation, i.e., by loss of dense foci of constitutive heterochromatin. These results suggest that chromatin is decondensed and that ATM is activated independently of DNA damage signaling pathways during the very early stages of apoptosis.
...
PMID:Early-stage apoptosis is associated with DNA-damage-independent ATM phosphorylation and chromatin decondensation in NIH3T3 fibroblasts. 1794 18

Cells respond to DNA double-strand breaks by recruiting factors such as the DNA-damage mediator protein MDC1, the p53-binding protein 1 (53BP1), and the breast cancer susceptibility protein BRCA1 to sites of damaged DNA. Here, we reveal that the ubiquitin ligase RNF8 mediates ubiquitin conjugation and 53BP1 and BRCA1 focal accumulation at sites of DNA lesions. Moreover, we establish that MDC1 recruits RNF8 through phosphodependent interactions between the RNF8 forkhead-associated domain and motifs in MDC1 that are phosphorylated by the DNA-damage activated protein kinase ataxia telangiectasia mutated (ATM). We also show that depletion of the E2 enzyme UBC13 impairs 53BP1 recruitment to sites of damage, which suggests that it cooperates with RNF8. Finally, we reveal that RNF8 promotes the G2/M DNA damage checkpoint and resistance to ionizing radiation. These results demonstrate how the DNA-damage response is orchestrated by ATM-dependent phosphorylation of MDC1 and RNF8-mediated ubiquitination.
...
PMID:Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. 1800 5

DNA and histone synthesis are coupled and ongoing replication is required to maintain histone gene expression. Here, we expose S phase-arrested cells to the kinase inhibitors caffeine and LY294002. This uncouples DNA replication from histone messenger RNA (mRNA) abundance, altering the efficiency of replication stress-induced histone mRNA down-regulation. Interference with caffeine-sensitive checkpoint kinases ataxia telangiectasia and Rad3 related (ATR)/ataxia telangiectasia mutated (ATM) does not affect histone mRNA down- regulation, which indicates that ATR/ATM alone cannot account for such coupling. LY294002 potentiates caffeine's ability to uncouple histone mRNA stabilization from replication only in cells containing functional DNA-activated protein kinase (DNA-PK), which indicates that DNA-PK is the target of LY294002. DNA-PK is activated during replication stress and DNA-PK signaling is enhanced when ATR/ATM signaling is abrogated. Histone mRNA decay does not require Chk1/Chk2. Replication stress induces phosphorylation of UPF1 but not hairpin[corrected]-binding protein/stem-loop binding protein at S/TQ sites, which are preferred substrate recognition motifs of phosphatidylinositol 3-kinase-like kinases, which indicates that histone mRNA stability may be directly controlled by ATR/ATM- and DNA-PK-mediated phosphorylation of UPF1.
...
PMID:DNA-activated protein kinase functions in a newly observed S phase checkpoint that links histone mRNA abundance with DNA replication. 1815 34

DNA damage by ionizing radiation (IR) can induce activations of both NF-kappaB and p53 through the upstream kinase ataxia telangiectasia mutated (ATM). NF-kappaB activation could also be signaled through two distinct or overlapped pathways; IkappaB kinases (IKKs)-IkappaBalpha and Akt-glycogen synthase kinase-3 (GSK-3). In the present study, however, we show that activation of Akt1 and the subsequent phosphorylation and inactivation of GSK-3beta by IR could also occur in ATM-deficient AT5BIVA cells as well as in normal MRC5CV1 fibroblasts. Similarly, lithium chloride (LiCl) was found to increase the phosphorylation of GSK-3beta independently of ATM. Transfection with either wild-type or kinase dead mutant GSK-3beta to the cells further indicated that phosphorylations of Akt1 and GSK-3beta were closely associated with the transcriptional transactivation of NF-kappaB in response to ionizing radiation. On the other hand, LiCl, having no effect on caspase-3 activation, significantly increased p53 phosphorylation and apoptotic death of the normal MRC5CV1 cells while IR, activating both caspase-3 and p53, profoundly affected AT5BIVA cell death. Hence, our data suggest that although ATM-mediated IKK-IkappaBalpha pathway might be a typical pathway for IR-induced NF-kappaB activation, GSK-3beta phosphorylation could also partially contribute to the transcriptional transactivation of NF-kappaB in an ATM-independent manner and that GSK-3beta phosphorylation could induce ATM-mediated cell apoptosis through the activation of p53.
...
PMID:Ionizing radiation can induce GSK-3beta phosphorylation and NF-kappaB transcriptional transactivation in ATM-deficient fibroblasts. 1824 62


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---