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)

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

Bleomycin is a redox-active drug with anticancer and other clinical applications. It is also frequently used as a tool in fundamental research on cellular responses to DNA double-strand breaks (DSBs). A conversion of bleomycin into its DNA-breaking form requires Fe, one-electron donors and O2. Here, we examined how a major biological antioxidant ascorbate (reduced vitamin C), which is practically absent in standard cell culture, impacts cellular responses to bleomycin. We found that restoration of physiological levels of vitamin C in human cancer cells increased their killing by bleomycin in 2D cultures and 3D tumor spheroids. Higher cytotoxicity of bleomycin occurred in cells with normal and shRNA-depleted p53. Cellular vitamin C enhanced the ability of bleomycin by produce DSBs, which was established by direct measurements of these lesions in three cell lines. Vitamin C-restored cancer cells also showed a higher sensitivity to killing by low-dose bleomycin in combination with inhibitors of DSB repair-activating ATM or DNA-PK kinases. The presence of ascorbate in bleomycin-treated cells suppressed a DSB-independent activation of the ATM-CHK2 axis by blocking superoxide radical. In vitro studies detected a greatly superior ability of ascorbate over other cellular reducers to catalyze DSB formation by bleomycin. Ascorbate was faster than other antioxidants in promoting two steps in activation of bleomycin. Our results demonstrate strong activation effects of vitamin C on bleomycin, shifting its toxicity further toward DNA damage and making it more sensitive to manipulations of DNA repair.
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PMID:Vitamin C increases DNA breaks and suppresses DNA damage-independent activation of ATM by bleomycin. 3092 64

Cellular reduction of carcinogenic chromium(VI) causes several forms of Cr-DNA damage with different genotoxic properties. Chromate-treated cultured cells have shown a strong proapoptotic activity of the DNA damage-sensitive transcription factor p53. However, induction of p53 transcriptional targets by Cr(VI) in rodent lungs was weak or undetectable. We examined Cr(VI) effects on the p53 pathway in human cells with restored levels of ascorbate that acts as a principal reducer of Cr(VI) in vivo but is nearly absent in standard cell cultures. Ascorbate-restored H460 and primary human cells treated with Cr(VI) contained higher levels of p53 and its Ser15 phosphorylation, which were induced by ATR kinase. Cr(VI)-stimulated p53 phosphorylation occurred in S-phase by a diffusible pool of ATR that was separate from the chromatin-bound pool targeting DNA repair substrates at the sites of toxic mismatch repair of Cr-DNA adducts. Even when more abundantly present than after exposure to the radiomimetic bleomycin, Cr(VI)-stabilized p53 showed a much more limited activation of its target genes in two types of primary human cells. No increases in mRNA were found for nucleotide excision repair factors and a majority of proapoptotic genes. A weak transcription activity of Cr(VI)-upregulated p53 was associated with its low lysine acetylation in the regulatory C-terminal domain, resulting from the inability of Cr(VI) to activate ATM in ascorbate-restored cells. Thus, p53 activation by ascorbate-metabolized Cr(VI) represents a limited genome-protective response that is defective in upregulation of DNA repair genes and proapoptotic transcripts for elimination of damaged cells.
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PMID:p53 activation by Cr(VI): a transcriptionally limited response induced by ATR kinase in S-phase. 3138 77