Hyperphosphorylation of histone H2A.X and dephosphorylation of histone H1 subtypes in the course of apoptosis

Talasz, Heribert; Helliger, Wilfried; Sarg, Bettina; Debbage, Paul; Puschendorf, Bernd; Lindner, Herbert

doi:10.1038/sj.cdd.4400925

Cited by 47 publications

(45 citation statements)

References 47 publications

(32 reference statements)

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“…In our study, we found that GSE causes DNA damage as evidenced by phosphorylation of H2A.X at Ser 139 as a function of time after GSE treatment. It is important to emphasize here that hyperphosphorylation of H2A.X strongly correlates to apoptotic chromatin fragmentation (40), suggesting that GSE causes DNA damage and associated apoptotic death of LNCaP cells.…”

Section: Discussionmentioning

confidence: 99%

Grape seed extract induces anoikis and caspase-mediated apoptosis in human prostate carcinoma LNCaP cells: possible role of ataxia telangiectasia mutated–p53 activation

Kaur¹,

Agarwal

2006

Molecular Cancer Therapeutics

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Prostate cancer is the second leading cancer diagnosed in elderly males in the Western world. Epidemiologic studies suggest that dietary modifications could be an effective approach in reducing various cancers, including prostate cancer, and accordingly cancer-preventive efficacy of dietary nutrients has gained increased attention in recent years. We have recently shown that grape seed extract (GSE) inhibits growth and induces apoptotic death of advanced human prostate cancer DU145 cells in culture and xenograft. Because prostate cancer is initially an androgen-dependent malignancy, here we used LNCaP human prostate cancer cells as a model to assess GSE efficacy and associated mechanisms. GSE treatment of cells led to their detachment within 12 hours, as occurs in anoikis, and caused a significant decrease in live cells mostly due to their apoptotic death. GSE-induced anoikis and apoptosis were accompanied by a strong decrease in focal adhesion kinase levels, but an increase in caspase-3, caspase-9, and poly(ADP-ribose) polymerase cleavage; however, GSE caused both caspase-dependent and caspase-independent apoptosis as evidenced by cytochrome c and apoptosis-inducing factor release into cytosol. Additional studies revealed that GSE causes DNA damage -induced activation of ataxia telangiectasia mutated kinase and Chk2, as well as p53 Ser 15 phosphorylation and its translocation to mitochondria, suggesting this to be an additional mechanism for apoptosis induction. GSE-induced apoptosis, cell growth inhibition, and cell death were attenuated by pretreatment with N-acetylcysteine and involved reactive oxygen species generation. Together, these results show GSE effects in LNCaP cells and suggest additional in vivo efficacy studies in prostate cancer animal models. [Mol Cancer Ther 2006;5(5):1265 -74]

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Section: Discussionmentioning

confidence: 99%

Grape seed extract induces anoikis and caspase-mediated apoptosis in human prostate carcinoma LNCaP cells: possible role of ataxia telangiectasia mutated–p53 activation

Kaur¹,

Agarwal

2006

Molecular Cancer Therapeutics

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“…Apoptosis is characterized by major changes in chromatin structure since chromatin is highly compacted and DNA is extensively cleaved. Recent data have shown that apoptosis is accompanied by global changes in histone modifications, such as phosphorylation or ubiquitination (1,7,25,32,36,41). Moreover, the activation of proapoptotic genes and the inactivation of antiapoptotic genes, which occur during apoptosis, are accompanied by specific changes in histone modifications at these promoters.…”

mentioning

confidence: 99%

Cleavage and Cytoplasmic Relocalization of Histone Deacetylase 3 Are Important for Apoptosis Progression

Escaffit

Vaute

Chevillard-Briet

et al. 2007

Molecular and Cellular Biology

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The apoptotic process is accompanied by major changes in chromatin structure and gene expression. The apoptotic genetic program is progressively set up with the inhibition of antiapoptotic genes and the activation of proapoptotic ones. Here, we show that the histone deacetylase 3 (HDAC-3), which is a known corepressor of many proapoptotic genes, is subjected to proteolytic cleavage during apoptosis in a cell type-and speciesindependent manner. This cleavage is caspase dependent and leads to the loss of the C-terminal part of HDAC-3. The cleaved form of HDAC-3 accumulates in the cytoplasm. Furthermore, we found that forced nuclear localization of HDAC-3 decreases the efficiency of apoptosis induction, indicating that HDAC-3 cytoplasmic relocalization is important for the apoptotic process. Finally, we observed that HDAC-3 cleavage allowed increased histone acetylation and transcriptional activation on a proapoptotic HDAC-3-target gene, the Fas-encoding gene. Altogether, our results thus indicate that HDAC-3 cleavage is crucial for efficient apoptosis induction because it allows the activation of some proapoptotic genes during apoptosis progression.

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“…During the initiation of DNA fragmentation that occurs during apoptosis, H2AX is also phosphorylated. This phosphorylation occurs with the appearance of high molecular weight DNA fragments but before the externalization of phosphatidyl-serine or the appearance of internucleosomal DNA fragments (20,21). Recent studies have provided some insight into the function of H2AX.…”

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confidence: 99%

ATR/ATM Targets Are Phosphorylated by ATR in Response to Hypoxia and ATM in Response to Reoxygenation

Hammond

Dorie

Giaccia

2003

Journal of Biological Chemistry

263

229

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The ATR kinase phosphorylates both p53 and Chk1 in response to extreme hypoxia (oxygen concentrations of less than 0.02%). In contrast to ATR, loss of ATM does not affect the phosphorylation of these or other targets in response to hypoxia. However, hypoxia within tumors is often transient and is inevitably followed by reoxygenation. We hypothesized that ATR activity is induced under hypoxic conditions because of growth arrest and ATM activity increases in response to the oxidative stress of reoxygenation. Using the comet assay to detect DNA damage, we find that reoxygenation induced significant amounts of DNA damage. Two ATR/ATM targets, p53 serine 15 and histone H2AX, were both phosphorylated in response to hypoxia in an ATR-dependent manner. These phosphorylations were then maintained in response to reoxygenation-induced DNA damage in an ATM-dependent manner. The reoxygenation-induced p53 serine 15 phosphorylation was inhibited by the addition of N-acetyl-L-cysteine (NAC), indicating that free radical-induced DNA damage was mediated by reactive oxygen species. Taken together these data implicate both ATR and ATM as critical roles in the response of hypoxia and reperfusion in solid tumors.

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Hyperphosphorylation of histone H2A.X and dephosphorylation of histone H1 subtypes in the course of apoptosis

Cited by 47 publications

References 47 publications

Grape seed extract induces anoikis and caspase-mediated apoptosis in human prostate carcinoma LNCaP cells: possible role of ataxia telangiectasia mutated–p53 activation

Grape seed extract induces anoikis and caspase-mediated apoptosis in human prostate carcinoma LNCaP cells: possible role of ataxia telangiectasia mutated–p53 activation

Cleavage and Cytoplasmic Relocalization of Histone Deacetylase 3 Are Important for Apoptosis Progression

ATR/ATM Targets Are Phosphorylated by ATR in Response to Hypoxia and ATM in Response to Reoxygenation

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