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: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of cells to hypertonic medium after X-irradiation results in a 3-4-fold increase in the phosphorylation of histone H2AX (gammaH2AX) at sites of radiation-induced DNA double-strand breaks. This increase was previously associated with salt-induced radiosensitization and inhibition of repair of DNA double-strand breaks. To examine possible mechanisms for the increase in foci size, chemical inhibitors of kinase and phosphatase activity and cell lines deficient in ATM and DNA-PK, two kinases known to phosphorylate H2AX, were examined. H2AX kinase and phosphatase activity were maintained in the presence of high salt. ATM mutant HT144 melanoma cells showed the expected 3-4-fold increase in H2AX phosphorylation in the presence of 0.5M Na(+). However, DNA-PKcs deficient M059J cells failed to respond to hypertonic treatment and M059J Fus1 cells corrected for this deficiency showed the expected increase in foci size. Although the active phosphoform of ATM, phosphoserine-1981, increased after irradiation, the level was unaffected by the addition of 0.5M Na(+). Instead, 0.5M Na(+) caused a partial redistribution of serine-1981-ATM to perinuclear regions. Hypertonic medium added after irradiation was effective in inhibiting rejoining of the radiation-induced double-strand breaks even in DNA-PK deficient M059J cells. We suggest that hypertonic treatment following irradiation inhibits double-strand break rejoining that in turn maintains DNA-PK activity at the site of the break, enhancing the size of the gammaH2AX foci.
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PMID:DNA-PK is responsible for enhanced phosphorylation of histone H2AX under hypertonic conditions. 1604 94

Vitamin C has inconsistent effects on malignant tumor cells, which vary from growth stimulation to apoptosis induction. It is well known that melanoma cells are more susceptible to vitamin C than any other tumor cells, but the precise mechanism remains to be elucidated. In the present study, the proliferation of B16F10 melanoma cells was suppressed by vitamin C, which induced growth arrest in a dose-dependent manner without cytotoxic effects. Therefore, we investigated the changes in cell cycle distribution of B16F10 melanoma cells by staining DNAs with propidium iodide (PI). The growth inhibition of B16F10 melanoma by vitamin C was associated with an arrest of cell cycle distribution at G1 stage. In addition, the levels of p53-p21Waf1/Cip1 increased during G1 arrest, which were essential for vitamin C-induced cell cycle arrest. The increased p21Waf1/Cip1 inhibited CDK2. Moreover, the activity of p53-p21Waf1/Cip1 pathway was closely related with the activation of checkpoint kinase 2 (Chk2). Inhibitor of the PI3K-family, LY294002 and the ATM/ATR inhibitor, caffeine, blocked vitamin C-induced growth arrest in B16F10 melanoma cells. These results suggest that vitamin C might be a potent agent to inhibit proliferative activity of melanoma cells via the regulation of Chk2-p53-p21Waf1/Cip1 pathway.
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PMID:The molecular mechanisms of vitamin C on cell cycle regulation in B16F10 murine melanoma. 1745 38

ING (inhibitor of growth) tumor suppressors regulate cell-cycle checkpoints, apoptosis, and ultimately tumor suppression. Among the ING family members, p33(ING1b) is the most intensively studied and plays an important role in the cellular stress response to DNA damage. Here we demonstrate that there is basal phosphorylation of p33(ING1b) at Ser-126 in normal physiological conditions and that this phosphorylation is increased on DNA damage. The mutation of Ser-126 to alanine dramatically shortened the half-life of p33(ING1b). Furthermore, we found that both Chk1 and Cdk1 can phosphorylate this residue. Interestingly, while Cdk1 can phosphorylate p33(ING1b) at Ser-126 in nonstress conditions, Chk1 predominantly phosphorylates this residue on DNA damage, which suggests that p33(ING1b) is a downstream target of the ATM/ATR response cascade to genotoxic stress. More importantly, our data indicate that the Ser-126 residue plays a key role in regulating the expression of cyclin B1 and proliferation of melanoma cells.
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PMID:Phosphorylation of the tumor suppressor p33(ING1b) at Ser-126 influences its protein stability and proliferation of melanoma cells. 1758 55

The deep penetrating nevus (DPN) is a variant of benign melanocytic nevus with clinical and histologic features mimicking vertical growth phase, nodular malignant melanoma (NMM). Because fatal misdiagnosis such as NMM occurs in 29% to 40% of the DPN, molecular differentiation markers are highly desirable. Beyond the clinical demand for precise diagnosis and diagnosis-adapted, preventive therapeutic strategies, the DPN represents a valuable natural model for melanocytic invasion without metastatic potential that per se deserves further investigations. In the present study, at first, we used a genome-wide, microarray-based approach to systematically prescreen for possible molecular markers differentially expressed between selected cases of typical DPN (n=4) and metastatic NMM controls (n=4). Gene expression profiling was done on Affymetrix Human X3P microarrays. Of the 47,000 genes spotted, we identified a list of 227 transcripts, which remained significantly regulated at a false discovery rate of 5%. Subsequently, we verified the expression of a subset of the most interesting transcripts in a larger immunohistochemical series (DPN, n=17; NMM, n=16). Of these transcripts, three were selected for immunohistochemical confirmation: tissue inhibitor of metalloproteinase-2, tumor protein D52, and ataxia telangiectasia-mutated gene (ATM). Additional criteria for selection from the list of 227 significantly regulated transcripts were grouping into functional Ingenuity networks and a known melanoma- or cancer-relevant function. Following these criteria, we detected a highly significant up-regulation of ATM transcription in NMM, which was also mirrored by ATM protein up-regulation. In contrast to the other markers, ATM particularly might serve as a suitable diagnostic and reliable discriminator of DPN/NMM because ATM immunoreactivity also showed a reliable staining consistency within all samples of both entities.
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PMID:Ataxia telangiectasia-mutated gene is a possible biomarker for discrimination of infiltrative deep penetrating nevi and metastatic vertical growth phase melanoma. 1800 41

The incidence of melanoma continues to dramatically increase in most Western countries with predominantly Caucasian populations. However, only limited therapies for the metastatic stage of the disease are currently available. The main purpose of this study is to determine approaches that can substantially increase radiosensitivity of melanoma cells. The PI3K-AKT, NF-kappaB and COX-2 pathways, which are involved in the radioprotective response, are highly active in melanoma cells. Pharmacological suppression of COX-2 and PI3K-AKT, or RNAi-mediated knockdown of COX-2, substantially increased levels of G2/M arrest of the cell cycle and decreased clonogenic survival of gamma-irradiated melanomas, predominantly via a necrotic mechanism. On the other hand, resveratrol, a polyphenolic phytoalexin, selectively targets numerous cell signaling pathways, decreasing clonogenic survival primarily via an apoptotic mechanism. In melanoma cells, resveratrol inhibits STAT3 and NF-kappaB-dependent transcription, culminating in suppression of cFLIP and Bcl-xL expression, while activating the MAPK- and the ATM-Chk2-p53 pathways. Resveratrol also upregulates TRAIL promoter activity and induces TRAIL surface expression in some melanoma cell lines, resulting in a rapid development of apoptosis. Sequential treatment of melanoma cells, first with gamma-irradiation to upregulate TRAIL-R surface expression, and then with resveratrol to suppress antiapoptotic proteins cFLIP and Bcl-xL and induce TRAIL surface expression, had dramatic effects on upregulation of apoptosis in some melanoma lines, including SW1 and WM35. However, for melanoma lines exhibiting suppressed translocation of TRAIL to the cell surface, a necrotic mechanism of cell death was primarily involved in radiation response. Hence, surface expression of TRAIL induced by resveratrol appears to be a decisive event, one which determines an apoptotic versus a necrotic response of melanoma cells to sequential treatment.
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PMID:Radiosensitization of melanoma cells through combined inhibition of protein regulators of cell survival. 1845 17

The Erbb2 receptor is activated by UV irradiation, the primary cause of non-melanoma skin cancer. We hypothesized that Erbb2 activation contributes to UV-induced skin tumorigenesis by suppressing cell cycle arrest. Consistent with this hypothesis, inhibition of Erbb2 in v-ras(Ha) transgenic mice before UV exposure resulted in both 56% fewer skin tumors and tumors that were 70% smaller. Inhibition of the UV-induced activation of Erbb2 also resulted in milder epidermal hyperplasia, S-phase accumulation, and decreased levels of the cell cycle regulator Cdc25a, suggesting altered cell cycle regulation on inhibition of Erbb2. Further investigation using inhibition or genetic deletion of Erbb2 in vitro revealed reduced Cdc25a levels and increased S-phase arrest in UV-irradiated cells lacking Erbb2 activity. Ectopic expression of Cdc25a prevented UV-induced S-phase arrest in keratinocytes lacking Erbb2 activity, demonstrating that maintenance of Cdc25a by Erbb2 suppresses cell cycle arrest. Examination of checkpoint pathway activation upstream of Cdc25a revealed Erbb2 activation did not alter Ataxia Telangiectasia and Rad3-related/Ataxia Telangiectasia Mutated activity but increased inhibitory phosphorylation of Chk1-Ser(280). Since Akt phosphorylates Chk1-Ser(280), the effect of Erbb2 on phosphatidyl inositol-3-kinase (PI3K)/Akt signaling during UV-induced cell cycle arrest was determined. Erbb2 ablation reduced the UV-induced activation of PI3K while inhibition of PI3K/Akt increased UV-induced S-phase arrest. Thus, UV-induced Erbb2 activation increases skin tumorigenesis through inhibitory phosphorylation of Chk1, Cdc25a maintenance, and suppression of S-phase arrest via a PI3K/Akt-dependent mechanism.
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PMID:Erbb2 suppresses DNA damage-induced checkpoint activation and UV-induced mouse skin tumorigenesis. 1940 93

Cytotoxicity and apoptosis induced by etoposide were studied during 72 hr in human melanoma cells. Etoposide initiated DNA-damage signaling via ATM kinase and activated p53 pathway and caspase-2. In response to treatment with etoposide, mitochondria of melanoma cells first increased their abundance and activity, and at later treatment intervals their dynamic behavior and functions became suppressed. Observed mitochondrial perturbation was not preceded by membrane potential loss but cytochrome c release was observed together with a rise in caspase-9 and caspase-3 activities. The pharmacological inhibition of relevant induced targets proved the importance of ATM and caspase-2 in etoposide-mediated cytotoxicity and apoptosis.
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PMID:Cytotoxicity and mitochondrial apoptosis induced by etoposide in melanoma cells. 1948 5

Melanoma in its advanced stages is resistant not only to chemotherapy but also to radiation treatment. In line with efforts to identify genes that are key regulators of the disease and as such, may prove valuable targets for adjuvant and neo-adjuvant therapy of melanomas, we previously reported the presence of Serial Analysis of Gene Expression (SAGE) tags, corresponding to the Ataxia Telangiectasia Mutated (ATM) gene, in SAGE libraries generated from tissues representing primary and metastatic melanomas. In the present study, we document that ATM is expressed at high levels in advanced-stage melanomas. Given its crucial role in the cellular response to DNA double-strand breaks (DSB), ionizing radiation, and UV damage, we pursued a series of functional studies involving the targeting of ATM by way of RNA interference or an ATM-specific small-molecule inhibitor, followed by exposure of the cells to ionizing radiation or radiation combined with a DNA-intercalating drug, to test the hypothesis that the high-level expression of ATM prevents melanoma cells from undergoing apoptosis in response to DNA DSB-inducing treatments. However, unlike as demonstrated in the case of other malignancies, our findings summarized herein do not point to ATM as a pivotal DNA damage sensor for advanced-stage melanomas, raising the possibility that in these cells, genes other than ATM regulate and control the repair of DNA DSB.
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PMID:Suppressing the high-level expression and function of ATM in advanced-stage melanomas does not sensitize the cells to ionizing radiation. 1968 76

Telomere homolog oligonucleotides (T-oligos) activate an innate telomere-based program that leads to multiple anticancer effects. T-oligos act at telomeres to initiate signaling through the Werner protein and ATM kinase. We wanted to determine if T-oligos have antiangiogenic effects. We found that T-oligo-treated human melanoma (MM-AN) cells had decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor 2, angiopoeitin-1 and -2 and decreased VEGF secretion. T-oligos activated the transcription factor E2F1 and inhibited the activity of the angiogenic transcription factor, HIF-1alpha. T-oligos inhibited EC tubulogenesis and total tumor microvascular density matrix invasion by MM-AN cells and ECs in vitro. In melanoma SCID xenografts, two systemic T-oligo injections decreased by 60% (P < .004) total tumor microvascular density and the functional vessels density by 80% (P < .002). These findings suggest that restriction of tumor angiogenesis is among the host's innate telomere-based anticancer responses and provide further evidence that T-oligos may offer a powerful new approach for melanoma treatment.
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PMID:Inhibition of melanoma angiogenesis by telomere homolog oligonucleotides. 2065 8

The tumor suppressor gene TP53, encoding the p53 protein, has its gene locus on the short arm of chromosome 17 p13.1 (1,2). p53 has been denoted "guardian of the genome" (3) owing to its essential cellular functions in apoptosis control, cell-cycle control, chromosomal segregation, gene transcription, and genomic stability (4). The gene encodes a protein of 393 amino acids (5). The tertiary structure of the p53 protein is known to a relatively large extent; the DNA binding region has been localized to amino acids 102 to 292. Murine double minute-2 (MDM2) binds to the amino terminal of the p53 protein and is a negative regulator of p53 (6). p53 is normally activated by ultraviolet (UV)-light, radiation, cytostatics, and carcinogens. The activation by these may involve interaction with the ataxia telangiectasia gene (ATM). The p53 gene can be inactivated by somatic or germ-line mutations. Somatic mutations in the p53 gene is the most common genetic abnormality so far described in human cancer (7). Patients with germ-line p53 mutation's are part of the Li-Fraumeni syndrome. These patients have an increased risk of developing adrenocortical, breast, gastrointestinal tract, and lung carcinoma, as well as soft-tissue sarcoma and malignant melanoma (8,9). Studies on mice have revealed that induced deficiency of both alleles of the p53 gene is associated within an increased risk of lymphomas and sarcomas (10). p53 can also be inactivated by certain viral oncoproteins, such as human papilloma virus protein E6, SV40 large T-antigen, hepatitis B viral X protein, and adenovirus protein E1B (4).
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PMID:Analysis of the p53 Status of Tumors : An Overview of Methods. 2137 38


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