Involvement of ASK1 in Ca<sup>2+</sup>‐induced p38 MAP kinase activation

Takeda, Kohsuke; Matsuzawa, Atsushi; Nishitoh, Hideki; Tobiume, Kei; Kishida, Satoshi; Ninomiya‐Tsuji, Jun; Matsumoto, Kunihiro; Ichijo, Hidenori

doi:10.1038/sj.embor.7400072

Cited by 171 publications

(116 citation statements)

References 23 publications

(33 reference statements)

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“…Ca 2ϩ /calmodulin-dependent protein kinase II activates ASK1 by phosphorylation in neurons (32,33). In our study, however, KN-93, an inhibitor of Ca 2ϩ /calmodulin-dependent protein kinase II, did not affect the potentiating effect of Ca 2ϩ influx on 6-OHDAinduced ASK1 activation (Fig.…”

Section: Discussioncontrasting

confidence: 50%

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CIB1 functions as a Ca ²⁺ -sensitive modulator of stress-induced signaling by targeting ASK1

Yoon¹,

Cho²,

Lee³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Calcium and integrin binding protein 1 (CIB1) is a Ca 2+ -binding protein of 22 kDa that was initially identified as a protein that interacts with integrin α IIb . Although it interacts with various proteins and has been implicated in diverse cellular functions, the molecular mechanism by which CIB1 regulates intracellular signaling networks has remained unclear. We now show that, by targeting apoptosis signal-regulating kinase 1 (ASK1), CIB1 negatively regulates stress-activated MAPK signaling pathways. CIB1 was thus shown to bind to ASK1, to interfere with the recruitment of TRAF2 to ASK1, and to inhibit the autophosphorylation of ASK1 on threonine-838, thereby blocking ASK1 activation. Furthermore, CIB1 mitigated apoptotic cell death initiated either by TNF-α in breast cancer MCF7 cells or by 6-hydroxydopamine (6-OHDA) in dopaminergic cells. Ca 2+ influx induced by membrane depolarization reversed the inhibitory effect of CIB1 on 6-OHDA-induced ASK1 activation and cell death in dopaminergic neurons. These observations thus suggest that CIB1 functions as a Ca 2+ -sensitive negative regulator of ASK1-mediated signaling events.

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Section: Discussioncontrasting

confidence: 50%

“…Several Ca 2ϩ /calmodulin-binding proteins have been associated with the regulation of ASKl activity (32)(33)(34). Ca 2ϩ /calmodulin-dependent protein kinase II activates ASK1 by phosphorylation in neurons (32,33).…”

Section: Discussionmentioning

confidence: 99%

CIB1 functions as a Ca ²⁺ -sensitive modulator of stress-induced signaling by targeting ASK1

Yoon¹,

Cho²,

Lee³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…As inhibition of p38MAPKa by the SB203580 compound or by short hairpin RNA interference obstructed 5-FU-associated apoptosis while autophagy was promoted, p38MAPK was suggested to act as a potential regulator of p53 and the balance between apoptotic and autophagic processes. 32 In turn, the mammalian mitogen-activated protein (MAP3K) apoptosis signalregulating kinase 1 (ASK1) is a pivotal component in cytokine-and stress-induced apoptosis, which may act as a critical intermediate of Ca 2 þ signaling between Ca 2 þ -CaM-dependent protein kinase type II and p38MAPK 33,34 It is, therefore, possible that the Ca 2 þ -dependent apoptotic pathway disclosed by our data merges with the previously defined p38MAPK pathway. 32 To verify this hypothesis, 5-FU-treated HCT116 cells were pre-incubated with BAPTA and the p38MAPKa inhibitor SB203580, either separately or in combination (Figure 7).…”

Section: -Fu-induced Ca 2 þ Deregulation Is Signaling Through a P38msupporting

confidence: 57%

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

et al. 2012

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5-Fluorouracil (5-FU) is an anti-metabolite that is in clinical use for treatment of several cancers. In cells, it is converted into three distinct fluoro-based nucleotide analogs, which interfere with DNA synthesis and repair, leading to genome impairment and, eventually, apoptotic cell death. Current knowledge states that in certain cell types, 5-FU-induced stress is signaling through a p53-dependent induction of tumor necrosis factor-receptor oligomerization required for death-inducing signaling complex formation and caspase-8 activation. Here we establish a role of calcium (Ca 2 þ ) as a messenger for p53 activation in response to 5-FU. Using a combination of pharmacological and genetic approaches, we show that treatment of colon carcinoma cells stimulates entry of extracellular Ca 2 þ through long lasting-type plasma membrane channels, which further directs posttranslational phosphorylation of at least three p53 serine residues (S15, S33 and S37) by means of calmodulin (CaM) activity. Obstructing this pathway by the Ca 2 þ -chelator BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) or by inhibitors of CaM efficiently reduces 5-FUinduced caspase activities and subsequent cell death. Moreover, ectopic expression of p53 S15A in HCT116 p53 À / À cells confirmed the importance of a Ca 2 þ -CaM-p53 axis in 5-FU-induced extrinsic apoptosis. The fact that a widely used therapeutic drug, such as 5-FU, is operating via this pathway could provide new therapeutic intervention points, or specify new combinatorial treatment regimes.

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“…A recent study from our group suggests that mibefradil inhibits Akt and mTORC2 signaling (4), indicating additional cross-talk of T-type Ca 2þ channels with intracellular prosurvival signaling pathways. It remains to be elucidated how p38-MAPK is activated in response to T-type Ca 2þ channel inhibition or knockdown, and what Ca 2þ -dependent factors transduce signals to either upstream MAP3K5 (ASK1) kinase (14) or directly to p38-MAPK.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, proteins downstream from activated CaMKII, such as mitogen-activated protein 3 kinase 5 (MAP3K5, also known as apoptosis signal-regulating kinase 1 or ASK-1) or prosurvival protein kinase B (PKB also known as AKT) are affected by changes in intracellular Ca 2þ concentration (14)(15)(16). Increased CaM-KII activity regulates gene expression directly through phosphorylation of transcription factors, such as cyclic-AMP response element binding protein (CREB; reviewed in ref.…”

Section: Introductionmentioning

confidence: 99%

T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells

Dziegielewska

Brautigan

Larner

et al. 2014

Molecular Cancer Research

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Epithelial tumor cells express T-type Ca 2þ channels, which are thought to promote cell proliferation. This study investigated the cellular response to T-type Ca 2þ channel inhibition either by small-molecule antagonists or by RNAi-mediated knockdown. Selective T-type Ca 2þ channel antagonists caused growth inhibition and apoptosis more effectively in HCT116 cells expressing wild-type p53 (p53wt), than in HCT116 mutant p53 À/À cells. These antagonists increased p53-dependent gene expression and increased genomic occupancy of p53 at specific target sequences. The knockdown of a single T-type Ca 2þ channel subunit (CACNA1G) reduced cell growth and induced caspase-3/7 activation in HCT116 p53wt cells as compared with HCT116 mutant p53 À/À cells. Moreover, CaCo2 cells that do not express functional p53 were made more sensitive to CACNA1G knockdown when p53wt was stably expressed. Upon T-type Ca 2þ channel inhibition, p38-MAPK promoted phosphorylation at Ser392 of p53wt. Cells treated with the inhibitor SB203580 or specific RNAi targeting p38-MAPKa/b (MAPK14/MAPK11) showed resistance to T-type Ca 2þ channel inhibition. Finally, the decreased sensitivity to channel inhibition was associated with decreased accumulation of p53 and decreased expression of p53 target genes, p21Cip1 (CDKN1A) and BCL2-binding component 3 (BBC3/PUMA).

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Involvement of ASK1 in Ca²⁺‐induced p38 MAP kinase activation

Cited by 171 publications

References 23 publications

CIB1 functions as a Ca ²⁺ -sensitive modulator of stress-induced signaling by targeting ASK1

CIB1 functions as a Ca ²⁺ -sensitive modulator of stress-induced signaling by targeting ASK1

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells

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Involvement of ASK1 in Ca2+‐induced p38 MAP kinase activation

Cited by 171 publications

References 23 publications

CIB1 functions as a Ca 2+ -sensitive modulator of stress-induced signaling by targeting ASK1

CIB1 functions as a Ca 2+ -sensitive modulator of stress-induced signaling by targeting ASK1

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells

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Involvement of ASK1 in Ca²⁺‐induced p38 MAP kinase activation

CIB1 functions as a Ca ²⁺ -sensitive modulator of stress-induced signaling by targeting ASK1

CIB1 functions as a Ca ²⁺ -sensitive modulator of stress-induced signaling by targeting ASK1