Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P16104 (H2AX)
 3,930 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone deacetylase inhibitory prodrugs that are metabolized to carboxylic acid(s) and aldehyde(s) possess antineoplastic properties. Formaldehyde-releasing prodrugs were shown to be the most potent. The objective of this study was to gain understanding on the mode of action of these prodrugs in cancer cells. HL-60 and MCF-7 cells in the presence of N-acetylcysteine or glutathione were protected from death induced by formaldehyde-releasing prodrugs but not from death caused by the homologous acetaldehyde-releasing ones. Cell death induced by the former was accompanied by depletion of intracellular glutathione and increased reactive oxygen species that were attenuated by N-acetylcysteine. At fourfold higher concentration, acetaldehyde-releasing prodrugs increased reactive oxygen species that were further augmented by N-acetylcysteine. In HL-60 cells, formaldehyde-releasing prodrugs dissipated the mitochondrial membrane potential and glutathione or N-acetylcysteine restored it. Although acetaldehyde-releasing prodrugs dissipated mitochondrial membrane potential, it occurred at 20-fold greater concentration and was unaffected by the antioxidants. Formaldehyde-releasing prodrugs abrogated c-myc protein expression and elevated c-Jun and H2AX phosphorylation, N-acetylcysteine partially reversed these changes. Herein, we show that formaldehyde-releasing prodrugs diminish the level of glutathione most likely by forming S-formylglutathione adducts resulting in increase of reactive oxygen species followed by signaling events that lead to cancer cells death.
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PMID:Formaldehyde-releasing prodrugs specifically affect cancer cells by depletion of intracellular glutathione and augmentation of reactive oxygen species. 1803 Apr 72

The cell cycle inhibitor p21(CDKN1A) induces cell cycle arrest under different conditions, including senescence and terminal differentiation. Still debated is its involvement in the reversible transition from proliferation to a non-dividing quiescent state (G(0)), in which a significant role has been attributed to cell cycle inhibitor p27(CDKN1B). Here we provide evidence showing that high p21 protein levels are necessary to enter and maintain the quiescence state following contact inhibition and growth factor withdrawal. In fact, entry into quiescence was impaired, both in human fibroblasts in which p21 gene has been deleted, or protein expression knocked-down by RNA interference. Importantly, in the absence of p21, human fibroblasts activate a DNA damage-like signalling pathway, as shown by phosphorylation of histone H2AX and Chk1 proteins. In addition, we show that in the absence of p21, checkpoint is activated by an unscheduled entry into S phase, with a reduced efficiency in DNA maturation, in the presence of high c-myc protein levels. These results highlight the role of p21 in counteracting inappropriate proliferation stimuli for genome stability maintenance.
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PMID:Loss of p21 CDKN1A impairs entry to quiescence and activates a DNA damage response in normal fibroblasts induced to quiescence. 1910 7