Serum starvation induces H2AX phosphorylation to regulate apoptosis via p38 MAPK pathway

Lu, Cheng; Shi, Ying; Wang, Zhe; Song, Zhihong; Zhu, Mei-Cai; Cai, Qing-Qing; Chen, Tao

doi:10.1016/j.febslet.2008.06.051

Cited by 85 publications

(68 citation statements)

References 17 publications

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“…5A), suggesting that the cell volume decrease of PMC prior to mitosis is detected by a checkpoint that can be triggered in cells not achieving PMC to activate the p38 pathway and prevent mitotic entry. The reduced level of phospho-H2AX in control cells with SB203580 compared with DMSO treatment is consistent with the reported function of p38 to directly phosphorylate H2AX (Lu et al 2008). The p42/p44 ERK pathway was only modestly affected by EAG2 knockdown and changes to p38 pathway activity (Fig.…”

Section: Eag2 Knockdown Results In a Striking Increase In Cell Volumesupporting

confidence: 76%

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

et al. 2012

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Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.

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Section: Eag2 Knockdown Results In a Striking Increase In Cell Volumesupporting

confidence: 76%

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

et al. 2012

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“…hGal9 also induced H2AX phosphorylation, which is critical for apoptosis by JNK activation or p38 MAPK activation (Figure 3a). [21][22][23][24] Conversely, neither JNK nor p38 activation was observed in myeloma cell lines those are resistant to hGal9-induced cell death (Supplementary Figure 7). Next, KMS-12-BM and IM9 cells were preincubated with 20 mM JNKinhibitor VIII and/or 20 mM SB203580 for 2 h and then treated with 100 nM hGal9 for 48 h. Neither JNK-inhibitor VIII nor SB203580 alone decreased the cell viability of two cell lines.…”

Section: Resultsmentioning

confidence: 99%

Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways

et al. 2010

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Galectins constitute a family of lectins that specifically exhibit the affinity for b-galactosides and modulate various biological events. Galectin-9 is a tandem-repeat type galectin with two carbohydrate recognition domains and has recently been shown to have an anti-proliferative effect on cancer cells. We investigated the effect of recombinant protease-resistant galectin-9 (hGal9) on multiple myeloma (MM). In vitro, hGal9 inhibited the cell proliferation of five myeloma cell lines examined, including a bortezomib-resistant subcell line, with IC 50 between 75.1 and 280.0 nM, and this effect was mediated by the induction of apoptosis with the activation of caspase-8, -9, and -3. hGal9-activated Jun NH 2 -terminal kinase (JNK) and p38 MAPK signaling pathways followed by H2AX phosphorylation. Importantly, the inhibition of either JNK or p38 MAPK partly inhibited the anti-proliferative effect of hGal9, indicating the crucial role of these pathways in the anti-MM effect of hGal9. hGal9 also induced cell death in patient-derived myeloma cells, some with poor-risk factors, such as chromosomal deletion of 13q or translocation t(4;14)(p16;q32). Finally, hGal9 potently inhibited the growth of human myeloma cells xenografted in nude mice. These suggest that hGal9 is a new therapeutic target for MM that may overcome resistance to conventional chemotherapy.

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“…21 Lu et al also showed that H2AX phosphorylation is required for serum starvation-induced apoptosis and have implicated p38-MAP kinase in this process. 22 On the other hand, H2AX-deficient fibroblasts are more sensitive to etoposide; 23 H2AX knockout mice are more sensitive to ionizing radiations; 24 and H2AX-null cells are hypersensitive to DNA alkylating agents, suggesting that H2AX confers cellular protection against alkylation-induced DNA damage. 25 Likewise, knockdown of H2AX in HCT116 cells enhances oxaliplatin-induced cell death (cell viability determined by MTT assay).…”

Section: Protein Kinases Implicated In the Apoptotic γ-H2ax Responsementioning

confidence: 99%

The apoptotic ring: A novel entity with phosphorylated histones H2AX and H2B, and activated DNA damage response kinases

Solier

Pommier²

2009

Cell Cycle

111

100

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Serum starvation induces H2AX phosphorylation to regulate apoptosis via p38 MAPK pathway

Cited by 85 publications

References 17 publications

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways

The apoptotic ring: A novel entity with phosphorylated histones H2AX and H2B, and activated DNA damage response kinases

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