Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ataxia telangiectasia (AT), a human hereditary disorder resulting from mutations in the ATM gene, is characterized by a high incidence of lymphoid malignancies, neurodegeneration, immunodeficiency, premature aging, elevated radiosensitivity, and genomic instability. Evidence has been accumulating that ATM-deficient cells are in a continuous state of oxidative stress. A variety of markers of oxidative stress were detected in AT patients as well as Atm-deficient mice, used as an animal model of AT. Since then, it has been proposed that oxidative stress contributes to the clinical phenotype of AT, especially carcinogenesis and neurodegeneration, and several animal studies were conducted to determine whether exogenous antioxidants mitigate the symptoms of AT. Tempol, EUK-189, and N-acetyl cysteine have been tested as chemopreventive antioxidants in Atm-deficient mice. We review these findings, mainly focusing on the effect of N-acetyl cysteine, which is known as a safe and efficient drug and nutritional supplement.
 ...
PMID:Antioxidants suppress lymphoma and increase longevity in Atm-deficient mice. 1718 31

Etoposide (VP-16) belongs to the family of DNA topoisomerase II (topo2) inhibitors, drugs widely used in cancer chemotherapy. Their presumed mode of action is stabilization of "cleavable complexes" between topo2 and DNA; collisions of DNA replication forks with these complexes convert them into DNA double-strand breaks (DSBs), potentially lethal lesions that may trigger apoptosis. Immunocytochemical detection of activation of ATM (ATM-S1981P) and histone H2AX phosphorylation (gammaH2AX) provides a sensitive probe of the induction of DSBs in individual cells. Using multiparameter cytometry we measured the expression of ATM-S1981P and gammaH2AX as well as initiation of apoptosis (caspase-3 activation) in relation to the cell cycle phase in etoposide-treated human lymphoblastoid TK6 cells. The induction of ATM-S1981P and gammaH2AX was seen in all phases of the cell cycle. The G(1)-phase cells, however, preferentially underwent apoptosis. The extent of etoposide-induced H2AX phosphorylation was partially reduced by N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS). The maximal reduction of H2AX phosphorylation by NAC, seen in G(1)-phase cells, was nearly 50%. NAC also protected a fraction of G(1) cells from etoposide-induced apoptosis, but had no such effect on S or G(2)M cells. However, no significant rise in the intracellular level of ROS upon treatment with etoposide was detected. The effects of etoposide were compared with the previously investigated effects of another topo2 inhibitor, mitoxantrone. The latter was seen to induce a maximal level of ATM-S1981P and gammaH2AX (partially abrogated by NAC) in G(1)-phase cells, but unlike etoposide, triggered apoptosis exclusively of S-phase cells. The data suggest that in addition to the generally accepted mechanism involving collisions of replication forks with the "cleavable complexes", other mechanisms which appear to be different for etoposide vs. mitoxantrone, may contribute to formation of DSBs and to triggering of apoptosis.
 ...
PMID:Induction of ATM activation, histone H2AX phosphorylation and apoptosis by etoposide: relation to cell cycle phase. 1729 10

The induction of senescence, an irreversible growth arrest, in cancer cells is regarded as a mean to halt tumor progression. The phytoalexin resveratrol (RV) is known to possess a variety of cancer-preventive, -therapeutic, and -chemosensitizing properties. We report here that chronic treatment with RV in a subapoptotic concentration induces senescence-like growth arrest in tumor cells. In contrast to the widely accepted antioxidant property of RV, we demonstrate that one causative stimulus for senescence induction by chronic RV is an increased level of reactive oxygen species (ROS). The ROS formed upon RV exposure include hydrogen peroxide and superoxide and originate largely from mitochondria. Consistently, co-incubation with the antioxidant N-acetyl cysteine interfered with RV-mediated reactivation of the senescence program. Molecular mediators on the way from increased ROS levels to the observed growth arrest include p38 MAPK, p53, and p21. Moreover, we provide evidence that RV-initiated replication stress, apparent by activation of the ataxia telangiectasia-mutated kinase pathway, is associated with increased ROS levels and senescence induction. This is the first report linking cell cycle effects with a pro-oxidant and pro-senescent effect of RV in cancer cells.
 ...
PMID:Chronic treatment with resveratrol induces redox stress- and ataxia telangiectasia-mutated (ATM)-dependent senescence in p53-positive cancer cells. 1762 9

Methylglyoxal (MG) is a reactive endogenous metabolite that is produced from the process of degradation of triose-phosphates. Under hyperglycemic conditions the rate of MG formation increases as a result of elevated concentrations of precursors. It has been established that MG elicits oxidative stress signaling, leading to the activation of MAP kinases, p38 MAPK and JNK, yet it remains largely unknown about a role of cell-cycle checkpoint regulation in MG-induced signaling. Here, we show that checkpoint kinases, Chk1 and Chk2, as well as their upstream ATM kinase are phosphorylated and activated following MG treatment of cultured cells. This MG-induced activation of Chk1 and Chk2 were inhibited by either aminoguanidine (AG), an inhibitor of production of advanced glycation end products (AGEs) or N-acetyl-l-cysteine (NAC), an anti-oxidant in dose dependent manners, indicating that oxidative stress via AGEs is involved critically in the activation of Chk1 and Chk2 by MG. Furthermore, it was found that cell-cycle synchronized cells exhibited G(2)/M checkpoint arrest following MG treatment, and that siRNA-mediated knock-down of Chk2, but not Chk1, results in a failure of MG-induced G(2)/M arrest. Thus, the results indicate a critical role for Chk2 in MG-induced G(2)/M cell-cycle checkpoint arrest.
 ...
PMID:Chk2 kinase is required for methylglyoxal-induced G2/M cell-cycle checkpoint arrest: implication of cell-cycle checkpoint regulation in diabetic oxidative stress signaling. 1766 21

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by immunodeficiency, neurodegeneration and cancer. The disease results from bi-allelic mutations in the AT mutated (ATM) gene involved in cell cycle checkpoint control and repair of DNA double-strand breaks. Evidence has been accumulating that oxidative stress is associated with AT and may be involved in the pathogenesis of the disease. This led to a hypothesis that antioxidants may alleviate the symptoms of AT. Consequently, several studies were conducted in Atm deficient mice to examine the role of antioxidants in cancer prevention and/or correction of neuromotor performance. N-acetyl-l-cysteine (NAC), EUK-189, tempol, and 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) have been tested in Atm deficient mice. In contrast to other antioxidants, NAC has been used in the clinical practice for many decades and is available as a dietary supplement. In this article, we review chemoprevention studies in Atm deficient mice and, in more detail, our findings on the effect of NAC. Our short-term study showed that NAC suppressed genome rearrangements linked to cancer. The long-term study demonstrated that NAC reduced the incidence and multiplicity of lymphoma and improved some aspects of motor performance.
 ...
PMID:Effects of antioxidants on cancer prevention and neuromotor performance in Atm deficient mice. 1803 53

Ultraviolet A (UVA) radiation represents more than 90% of the UV spectrum reaching Earth's surface. Exposure to UV light, especially the UVA part, induces the formation of photoexcited states of cellular photosensitizers with subsequent generation of reactive oxygen species (ROS) leading to damages to membrane lipids, proteins and nucleic acids. Although UVA, unlike UVC and UVB, is poorly absorbed by DNA, it inhibits cell cycle progression, especially during S-phase. In the present study, we examined the role of the DNA damage checkpoint response in UVA-induced inhibition of DNA replication. We provide evidence that UVA delays S-phase in a dose dependent manner and that UVA-irradiated S-phase cells accumulate in G2/M. We show that upon UVA irradiation ATM-, ATR- and p38-dependent signalling pathways are activated, and that Chk1 phosphorylation is ATR/Hus1 dependent while Chk2 phosphorylation is ATM dependent. To assess for a role of these pathways in UVA-induced inhibition of DNA replication, we investigated (i) cell cycle progression of BrdU labelled S-phase cells by flow cytometry and (ii) incorporation of [methyl-(3)H]thymidine, as a marker of DNA replication, in ATM, ATR and p38 proficient and deficient cells. We demonstrate that none of these pathways is required to delay DNA replication in response to UVA, thus ruling out a role of the canonical S-phase checkpoint response in this process. On the contrary, scavenging of UVA-induced reactive oxygen species (ROS) by the antioxidant N-acetyl-L-cystein or depletion of vitamins during UVA exposure significantly restores DNA synthesis. We propose that inhibition of DNA replication is due to impaired replication fork progression, rather as a consequence of UVA-induced oxidative damage to protein than to DNA.
 ...
PMID:Inhibition of S-phase progression triggered by UVA-induced ROS does not require a functional DNA damage checkpoint response in mammalian cells. 1900 Jul 90

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.
 ...
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 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.
 ...
PMID:Oxidative stress is linked to ERK1/2-p16 signaling-mediated growth defect in ATM-deficient astrocytes. 1932 50

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.
 ...
PMID:Loss of ATM impairs proliferation of neural stem cells through oxidative stress-mediated p38 MAPK signaling. 1954 30

We investigated the molecular effects of 3,4,2',4'-tetrahydroxychalcone (butein) treatment in two human hepatoma cancer cell lines-HepG2 and Hep3B. Butein treatment inhibited cancer cell growth by inducing G(2)/M phase arrest and apoptosis. Butein-induced G(2)/M phase arrest was associated with increased ATM, Chk1, and Chk2 phosphorylations and reduced cdc25C levels. Additionally, butein treatment enhanced inactivated phospho-Cdc2 levels, reduced Cdc2 kinase activity, and generated reactive oxygen species (ROS) that was accompanied by JNK activation. The extent of butein-induced G(2)/M phase arrest significantly decreased following pretreatment with N-acetyl-l-cysteine or glutathione and following JNK phosphorylation reduction by SP600125. Both N-acetyl-l-cysteine and glutathione also decreased butein-mediated apoptosis. Taken together, these results imply a critical role of ROS and JNK in the anticancer effects of butein.
 ...
PMID:Butein induces G(2)/M phase arrest and apoptosis in human hepatoma cancer cells through ROS generation. 1964 30


<< Previous 1 2 3 4 5 6 7 Next >>