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)

The mechanisms of sodium selenite-induced cell death in cervical carcinoma cells were studied during 24 h of exposure in the HeLa Hep-2 cell line. Selenite at the employed concentrations of 5 and 50 micromol/L produced time- and dose-dependent suppression of DNA synthesis and induced DNA damage which resulted in phosphorylation of histone H2A.X. These effects were influenced by pretreatment of cells with the SOD/catalase mimetic MnTMPyP or glutathione-depleting buthionine sulfoximine, suggesting the significant role of selenite-generated oxidative stress. Following the DNA damage, selenite activated p53-dependent pathway as evidenced by the appearance of phosphorylated p53 and accumulation of p21 in the treated cells. Concomitantly, selenite activated p38 pathway but its effect on JNK was very weak. p53- and p38-dependent signaling led to the accumulation of Bax protein, which was preventable by specific inhibitors of p38 (SB 203580) and p53 (Pifithrin-alpha). Mitochondria in selenite-treated cells changed their dynamics (shape and localization) and released AIF and Smac/Diablo, which initiated caspase-independent apoptosis as confirmed by the caspase-3 activity assay and the low effect of caspase inhibitors z-DEVD-fmk and z-VAD-fmk on cell death. We conclude that selenite induces caspase-independent apoptosis in cervical carcinoma cells mostly by oxidative stress-mediated activation of p53 and p38 pathways, but other selenite-mediated effects, in particular mitochondria-specific ones, are also involved.
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PMID:Selenium activates p53 and p38 pathways and induces caspase-independent cell death in cervical cancer cells. 1761 29

Although several proteins involved in mediating mitochondrial division have been reported in mammals, the mechanism of the fission machinery remains to be elucidated. Here, we identified a human nuclear gene (named MTGM) that encodes a novel, small, integral mitochondrial inner-membrane protein and shows high expression in both human brain tumor cell lines and tumor tissues. The gene is evolutionarily highly conserved, and its orthologs are 100% identical at the amino acid level in all analyzed mammalian species. The gene product is characterized by an unusual tetrad of the GxxxG motif in the transmembrane segment. Overexpression of MTGM (mitochondrial targeting GxxxG motif) protein results in mitochondrial fragmentation and release of mitochondrial Smac/Diablo to the cytosol with no effect on apoptosis. MTGM-induced mitochondrial fission can be blocked by a dominant negative Drp1 mutant (Drp1-K38A). Overexpression of MTGM also results in inhibition of cell proliferation, stalling of cells in S phase and nuclear accumulation of gamma-H2AX. Knockdown of MTGM by RNA interference induces mitochondrial elongation, an increase of cell proliferation and inhibition of cell death induced by apoptotic stimuli. In conclusion, we suggest that MTGM is an integral mitochondrial inner-membrane protein that coordinately regulates mitochondrial morphology and cell proliferation.
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PMID:The novel conserved mitochondrial inner-membrane protein MTGM regulates mitochondrial morphology and cell proliferation. 1953 34

A growing body of evidence indicates that valproic acid (VPA), a histone deacetylase inhibitor used to treat epilepsy and mood disorders, has histone deacetylase-related and -unrelated neurotoxic activity, the mechanism of which is still poorly understood. We report that VPA induces neuronal cell death through an atypical calpain-dependent necroptosis pathway that initiates with downstream activation of c-Jun N-terminal kinase 1 (JNK1) and increased expression of receptor-interacting protein 1 (RIP-1) and is accompanied by cleavage and mitochondrial release/nuclear translocation of apoptosis-inducing factor, mitochondrial release of Smac/DIABLO, and inhibition of the anti-apoptotic protein X-linked inhibitor of apoptosis (XIAP). Coinciding with apoptosis-inducing factor nuclear translocation, VPA induces phosphorylation of the necroptosis-associated histone H2A family member H2AX, which is known to contribute to lethal DNA degradation. These signals are inhibited in neuronal cells that express constitutively activated MEK/ERK and/or PI3-K/Akt survival pathways, allowing them to resist VPA-induced cell death. The data indicate that VPA has neurotoxic activity and identify a novel calpain-dependent necroptosis pathway that includes JNK1 activation and RIP-1 expression. A growing body of evidence indicates that valproic acid (VPA) has neurotoxic activity, the mechanism of which is still poorly understood. We report, for the first time, that VPA activates a previously unrecognized calpain-dependent necroptosis cascade that initiates with JNK1 activation and involves AIF cleavage/nuclear translocation and H2AX phosphorylation as well as an altered Smac/DIABLO to XIAP balance.
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PMID:Valproic acid induces neuronal cell death through a novel calpain-dependent necroptosis pathway. 2558 Dec 56