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

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

Cultured cells from patients inheriting the rare cancer-prone and radiotherapy-sensitive disorder ataxia telangiectasia (AT) exhibit defects in the activation of cell-cycle checkpoints after exposure to ionizing radiation. In particular, the failure of AT cells to arrest transiently the DNA de novo replication machinery immediately after irradiation--so-called radioresistant DNA synthesis (RDS)--is often taken as a molecular hallmark of the disease. Recently we reported that: (i) the radiation-responsive S-phase checkpoint operating in normal human cells is mediated by a signal transduction pathway involving Ca2+/calmodulin-dependent protein kinase II (CaMKII); and (ii) the RDS phenotype of AT cells is associated with failure to mobilize Ca2+ from intracellular stores, which is required for activation of the CaMKII-dependent S-phase arrest. In the present study, we demonstrate that the RDS phenotype of AT dermal fibroblasts can be rectified in the absence of ectopic expression of functional ATM, the 350-kDa protein kinase encoded by the gene mutated in AT. Correction of RDS was observed when AT fibroblasts were coincubated with normal fibroblasts under conditions in which the 2 different cell cultures shared the same medium but were completely separated physically. The RDS trait was also rectified when AT fibroblasts were briefly incubated with prostaglandin E2 in the absence of normal feeder cells, signifying that this ubiquitous eicosanoid can serve as the diffusible "RDS-correction factor" for AT cells in the aforementioned cocultivation studies. It would therefore appear that prostaglandin E2 can assume the role of an extracellular signaling modulator of the S-phase checkpoint in AT cells exposed to ionizing radiation, inducing DNA synthesis shutdown via an alternative, ATM-independent signal transduction pathway.
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PMID:Correction of radioresistant DNA synthesis in ataxia telangiectasia fibroblasts by prostaglandin E2 treatment. 1174 54

Ataxia-telangiectasia is a rare clinical disorder manifesting a variety of different abnormalities, including progressive neurodegeneration, increased cancer incidence, immune deficiency, sterility, and extreme radiosensitivity. Recent studies have demonstrated that the defective gene product in this disease, ATM, is a protein kinase. The identification of several different substrates for this kinase is beginning to explain the wide array of different physiologic abnormalities that occur when this gene product is dysfunctional. Since the ATM protein is a critical signaling molecule in the cellular response to ionizing irradiation, the identification of these substrates also results in elucidation of the steps involved in a number of different cellular signaling pathways initiated by irradiation. Such insights also result in the identification of potential new targets for enhancing the efficacy of radiation therapy.
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PMID:ATM--a key determinant of multiple cellular responses to irradiation. 1176 61

We have investigated the mechanism of S-phase arrest elicited by the carcinogen benzo(a)pyrene dihydrodiol epoxide (BPDE) in p53-deficient cells. Inhibition of DNA synthesis after BPDE treatment was rapid and dose dependent (approximately 50% inhibition after 2 h with 50 nM BPDE). Cells treated with low doses (50-100 nM) of BPDE resumed DNA synthesis after a delay of approximately 4-8 h, whereas cells that received high doses of BPDE (600 nM) failed to recover from S-phase arrest. The checkpoint kinase Chk1 (but not Chk2) was phosphorylated after treatment with low doses of BPDE. High concentrations of BPDE elicited phosphorylation of both Chk1 and Chk2. Adenovirus-mediated expression of "dominant-negative" Chk1 (but not dominant-negative Chk2) and the Chk1 inhibitor UCN-01 abrogated the S-phase delay elicited by low doses of BPDE. Consistent with a role for the caffeine-sensitive ATM or ATR protein kinase in low-dose BPDE-induced S-phase arrest, both Chk1 phosphorylation and S-phase arrest were abrogated by caffeine. However, low doses of BPDE elicited Chk1 phosphorylation and S-phase arrest in AT cells (from ataxia telangiectasia patients), demonstrating that ATM is dispensable for S-phase checkpoint responses to this genotoxin. BPDE-induced Chk1 phosphorylation and S-phase arrest were abrogated by caffeine treatment in AT cells, suggesting that a caffeine-sensitive kinase other than ATM is an important mediator of responses to BPDE-adducted DNA. Overall, our data demonstrate the existence of a caffeine-sensitive, Chk1-mediated, S-phase checkpoint that is operational in response to BPDE.
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PMID:Carcinogen-induced S-phase arrest is Chk1 mediated and caffeine sensitive. 1186 11

The human genetic disorder ataxia-telangiectasia (A-T) is due to lack of functional ATM, a protein kinase which is involved in cellular responses to DNA double strand breaks (DSBs) and possibly other oxidative stresses, as well as in regulation of several fundamental cellular functions. Studies regarding responses in A-T cells to the induction of DSBs utilize ionizing radiation or radiomimetic chemicals, such as neocarzinostatin (NCS), which induce DNA DSBs. This critical DNA lesion activates many defense systems, such as the cell cycle checkpoints. The cell cycle is also regulated through a timed and coordinated degradation of regulatory proteins via the ubiquitin pathway. Our recent studies indicate that the ubiquitin pathway is influenced by the cellular redox status and that it is the major cellular pathway for removal of oxidized proteins. Accordingly, we hypothesized that the absence of a functional ATM protein might involve perturbations to the ubiquitin pathway as well. We show here that upon treatment with NCS, there was a transient 50-70% increase in endogenous ubiquitin conjugates in A-T and wt lymphoblastoid cells. Ubiquitin conjugation capabilities per se and levels of substrates for conjugation were also similarly enhanced in wt and A-T cells upon NCS treatment. We also compared the ubiquitination response in A-T and wt cells using H(2)O(2) as the stress, in view of preexisting evidence of the effects of H(2)O(2) on ubiquitination capabilities in other types of cells. As with NCS treatment, there was an approximately 45% increase in endogenous ubiquitin conjugates by 2-4 h after exposure to H(2)O(2). Both cell types showed a rapid 50-150% increase in de novo formed 125I-ubiquitin conjugates. As compared with wt cells, unexposed A-T cells had higher endogenous levels of conjugates and enhanced conjugation capability. However, A-T cells mounted a more muted ubiquitination response to the stress. The enhanced ubiquitin conjugation in unstressed A-T cells and attenuated ability of these cells to respond to stress are consistent with the A-T cells being under oxidative stress and with their having an 'aged' phenotype. The indication that ubiquitin conjugate levels and ubiquitin conjugation capabilities are enhanced upon oxidative stress without significant changes in GSSG/GSH ratios indicates that assays of ubiquitination provide a sensitive measure of cellular stress. The data also add support to the impression that potentiated ubiquitination response to mild oxidative stress is a generalizable phenomenon.
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PMID:Ubiquitination capabilities in response to neocarzinostatin and H(2)O(2) stress in cell lines from patients with ataxia-telangiectasia. 1208 Apr 67

p53 plays an important role in response to ionizing radiation by regulating cell cycle progression and triggering apoptosis. These activities are controlled, in part, by the phosphorylation of p53 by the protein kinase ATM. Recent evidence indicates that the monofunctional DNA alkylating agent N-methyl-N'-nitro-N- nitrosoguanidine (MNNG) also triggers up-regulation and phosphorylation of p53; however, the mechanism(s) responsible for this are unknown. We observed that in MNNG-treated normal human fibroblasts, up-regulation and phosphorylation of p53 was sensitive to the ATM kinase inhibitor wortmannin. ATM-deficient fibroblasts exhibited a delay in p53 up-regulation indicating a role for ATM in triggering the MNNG-induced response. Likewise, a mismatch repair (MMR)-deficient colorectal tumor line failed to show rapid up-regulation of p53. However, unlike ATM-deficient cells, these MMR-deficient cells displayed rapid phosphorylation of the p53 residue serine 15 after MNNG. In vitro kinase assays indicate that ATM is rapidly activated in both normal and MMR-deficient cells in response to MNNG. Using a number of morphological and biochemical approaches, we failed to observe MNNG-induced apoptosis in normal human fibroblasts, suggesting that apoptosis-induced DNA strand breaks are not required for the activation of ATM in response to MNNG. Comet assays indicated that strand breaks accumulated, and p53 up-regulation/phosphorylation occurred quite rapidly (within 30 min) after MNNG treatment, suggesting that DNA strand breaks that arise during the repair process activate ATM. These findings indicate that ATM activation is not limited to the ionizing radiation-induced response and potentially plays an important role in response to DNA alkylation.
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PMID:ATM is activated in response to N-methyl-N'-nitro-N-nitrosoguanidine-induced DNA alkylation. 1215 94

Transposition in many organisms is regulated to control the frequency of DNA damage caused by the DNA breakage and joining reactions. However, genetic studies in prokaryotic systems have led to the isolation of mutant transposase proteins with higher or novel activities compared to those of the wild-type protein. In the course of our study of the effects of mutating potential ATM-family DNA damage checkpoint protein kinase sites in the Drosophila P-element transposase protein, we found one mutation, S129A, that resulted in an elevated level of transposase activity using in vivo recombination assays, including P-element-mediated germline transformation. In vitro assays for P-element transposase activity indicate that the S129A mutant exhibits elevated donor DNA cleavage activity when compared to the wild-type protein, whereas the strand-transfer activity is similar to that of wild type. This difference may reflect the nature of the in vitro assays and that normally in vivo the two reactions may proceed in concert. The P-element transposase protein contains 10 potential consensus phosphorylation sites for the ATM family of PI(3)-related protein kinases. Of these 10 sites, 8 affect transposase activity either positively or negatively when substituted individually with alanine and tested in vivo. A mutant transposase protein that contains all eight N-terminal serine and threonine residues substituted with alanine is inactive and can be restored to full activity by substitution of wild-type amino acids back at only 3 of the 8 positions. These data suggest that the activity of P-element transposase may be regulated by phosphorylation and demonstrate that one mutation, S129A, results in hyperactive transposition.
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PMID:Identification and analysis of a hyperactive mutant form of Drosophila P-element transposase. 1224 35

We have recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myeloma (MM) cells, inhibits binding of MM cells in the bone marrow microenvironment, and inhibits cytokines mediating MM cell growth, survival, drug resistance, and migration in vitro. PS-341 also inhibits human MM cell growth and prolongs survival in a SCID mouse model. Importantly, PS-341 has achieved remarkable clinical responses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH(2)-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2. Inhibition of JNK activity abrogates PS-341-induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies.
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PMID:Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. 1239

Maintenance of genome stability is essential for keeping cellular homeostasis. The DNA damage response is a central component in maintaining genome integrity. Among of the most cytotoxic DNA lesions are double strand breaks (DSBs) caused by ionizing radiation or radiomimetic chemicals. ATM is missing or inactivated in patients with ataxia-telangiectasia. Ataxia-telangiectasia patients display a pleiotropic phenotype and suffer primarily from progressive ataxia caused by degeneration of cerebellar Purkinje and granule neurons. Additional features are immunodeficiency, genomic instability, radiation sensitivity, and cancer predisposition. Disruption of the mouse Atm locus creates a murine model of ataxia-telangiectasia that exhibits most of the clinical features of the human disease but very mild neuronal abnormality. The ATM protein is a multifunctional protein kinase, which serves as a master regulator of cellular responses to DSBs. There is growing evidence that ATM may be involved in addition to the DSB response in other processes that maintain processes in cellular homeostasis. For example, mounting evidence points to increased oxidative stress in the absence of ATM. Here we report that the AP-1 pathway is constantly active in the brains of Atm-deficient mice not treated with DNA damaging agents. A canonical activation (increased phosphorylation of mitogen-activated protein kinase kinase-4, c-Jun N-terminal kinase, and c-Jun) of the AP-1 pathway was found in Atm-deficient cerebra, whereas induction of the AP-1 pathway in Atm-deficient cerebella is likely to mediate elevated expression of c-Fos and c-Jun. Although Atm(+/+) mice are capable of responding to ionizing radiation by activating stress responses such as the AP-1 pathway, Atm-deficient mice display higher basal AP-1 activity but gradually lose their ability to activate AP-1 DNA-binding activity in response to ionizing radiation. Our results further demonstrate that inactivation of the ATM gene results in a state of constant stress.
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PMID:Contribution of the Atm protein to maintaining cellular homeostasis evidenced by continuous activation of the AP-1 pathway in Atm-deficient brains. 1249 86

ATM is one of the sentries at the gate of genome stability. This multifunctional protein kinase orchestrates the intricate array of cellular responses to DNA double-strand breaks. Absence or inactivation of ATM leads to the pleiotropic genetic disorder ataxia-telangiectasia (A-T), whose hallmarks are neuronal degeneration, immunodeficiency, genomic instability, premature aging and cancer predisposition. Several features of the complex clinical and cellular phenotype of A-T are reminiscent of other syndromes involving neurodegeneration, premature aging or genomic instability. A common denominator of many of these conditions is the perturbation of the cellular balance of reactive oxygen species, which leads to constant oxidative stress. Of these disorders, ATM deficiency is one of the most extensively studied with regard to the genome instability-oxidative stress connection. This connection may provide new insights into the phenotypes associated with genetic deficiencies of DNA damage responses, and point to new strategies to alleviate some of their clinical symptoms.
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PMID:ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage. 1250 94

In contrast to yeast or mammalian cells, little is known about the signaling responses to DNA damage in plants. We previously characterized AtATM, an Arabidopsis homolog of the human ATM gene, which is mutated in ataxia telangiectasia, a chromosome instability disorder. The Atm protein is a protein kinase whose activity is induced by DNA damage, particularly DNA double-strand breaks. The phosphorylation targets of Atm include proteins involved in DNA repair, cell cycle control, and apoptosis. Here, we describe the isolation and functional characterization of two Arabidopsis mutants carrying a T-DNA insertion in AtATM. Arabidopsis atm mutants are hypersensitive to gamma-radiation and methylmethane sulfonate but not to UV-B light. In correlation with the radiation sensitivity, atm mutants failed to induce the transcription of genes involved in the repair and/or detection of DNA breaks upon irradiation. In addition, atm mutants are partially sterile, and we show that this effect is attributable to abundant chromosomal fragmentation during meiosis. Interestingly, the transcription of DNA recombination genes during meiosis was not dependent on AtATM, and meiotic recombination occurred at the same rate as in wild-type plants, raising questions about the function of AtAtm during meiosis in plants. Our results demonstrate that AtATM plays a central role in the response to both stress-induced and developmentally programmed DNA damage.
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PMID:AtATM is essential for meiosis and the somatic response to DNA damage in plants. 1250 17


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