Calpain small-1 modulates Akt/FoxO3A signaling and apoptosis through PP2A

Bertoli, Cosetta; Copetti, Tamara; Lam, Eric W.‐F.; Demarchi, Francesca; Schneider, Claudio

doi:10.1038/onc.2008.425

Cited by 56 publications

(60 citation statements)

References 50 publications

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“…Indeed it can regulate beta catenin signaling, 1 positively modulate autophagy to prevent accumulation of damaged proteins and organelles, 2 and beyond a certain level of stress it can cleave essential autophagic proteins, such DNA damage response links calpain to cellular senescence as ATG5, 3 and BECN1 (Copetti Unpublished), leading to an apoptotic switch. On the other hand calpain may negatively modulate p53-and FoxO3A-dependent apoptosis, 4,5 it activates NFκB-dependent survival signaling 6 and it can contribute to tumor cells survival due to its involvement in autophagy. Calpain depletion indeed sensitizes cells to nutrient withdrawal and genotoxic stress.…”

Section: Introductionmentioning

confidence: 99%

DNA damage response links calpain to cellular senescence

Demarchi¹,

Cataldo²,

Bertoli³

et al. 2010

Cell Cycle

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Section: Introductionmentioning

confidence: 99%

DNA damage response links calpain to cellular senescence

Demarchi¹,

Cataldo²,

Bertoli³

et al. 2010

Cell Cycle

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“…In under-nutrient conditions, changes in expression of various genes are seen in vitro and in vivo (Eriksson et al 2002;Anstead et al 2003;Vissers and Wilkie 2007;Bertoli et al 2009;Torii et al 2009). However, the correlation between fetal abnormalities associated with maternal undernutrition and changes in expression of transcription factors are not fully understood.…”

mentioning

confidence: 99%

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

Ito

Funamoto

Sato

et al. 2012

Tohoku J. Exp. Med.

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Maternal undernutrition during pregnancy is a risk factor for cerebrovascular and cardiovascular diseases in adulthood. Hypoxia-inducible factor 1 alpha (HIF1α) plays an essential role in cellular hypoxic responses, and its increased expression is associated with cerebrovascular and cardiovascular diseases. However, it is not known whether maternal undernutrition influences HIF1α expression in the fetal brain. We therefore analyzed the expression levels of HIF1α and its downstream genes in the fetal brain (day 17.5 of gestation, 1-2 days before birth). Maternal undernutrition did not noticeably affect the fetal body and brain weights. Both HIF1α mRNA and protein levels were increased in the brain under maternal undernutrition, despite the absence of hypoxia, as judged by the staining profile with hypoxyprobe-1 that identifies hypoxic cells. Importantly, maternal undernutrition caused the accumulation of HIF1α protein in oligodendrocyte precursor cells at the subventricular zone, a site of neurogenesis in the fetal brain. Maternal undernutrition also increased the mRNA level of mammalian target of rapamycin (mTOR), which could increase the level of HIF1α protein under normoxia. Furthermore, microarray analysis revealed that expression levels of mRNAs for 10 HIF1α downstream targets, including enolase 1 and hexokinase 1, were increased in the fetal brain under maternal undernutrition. Thus, the biochemical consequence of maternal undernutrition is similar to that of mild hypoxia. In conclusion, maternal undernutrition induces the expression of HIF1α in oligodendrocyte precursor cells at the subventricular zone, and it also induces the expression of hypoxia-related genes in the fetal brain probably via activation of the mTOR pathway.Keywords: fetal brain; hypoxia-inducible factor 1 alpha; hypoxic responses; mammalian target of rapamycin; maternal undernutrition Tohoku J. Exp. Med., 2012, 226 (1), 37-44.

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“…Pharmacological inhibition of calpain was previously shown to induce Akt phosphorylation in human neutrophils and monocytes, although no mechanism was described (42,43). However, another study showed that CAPNS1 knockout in mouse embryonic fibroblasts resulted in decreased Akt phosphorylation compared to wild-type cells when treated acutely with media free from amino acids and serum, and it was proposed that the phosphatase PP2A is a substrate of calpain (41). Our results indicate that the association between PI3K and calpain increases as serum starvation is prolonged; therefore, the PI3K-mediated effects of calpain on Akt phosphorylation that we observed are unlikely to occur during the short starvation treatments (up to 20 min) used by Bertoli et al (41).…”

Section: Discussionmentioning

confidence: 99%

“…However, another study showed that CAPNS1 knockout in mouse embryonic fibroblasts resulted in decreased Akt phosphorylation compared to wild-type cells when treated acutely with media free from amino acids and serum, and it was proposed that the phosphatase PP2A is a substrate of calpain (41). Our results indicate that the association between PI3K and calpain increases as serum starvation is prolonged; therefore, the PI3K-mediated effects of calpain on Akt phosphorylation that we observed are unlikely to occur during the short starvation treatments (up to 20 min) used by Bertoli et al (41). Taken together, these data reflect the complexity of the regulation of cell signaling in vivo and suggest that calpains may have a role in the regulation of multiple nodes of the signaling network.…”

Section: Discussionmentioning

confidence: 99%

“…1E). CAPNS1 was not the candidate with the highest fold change; however, it was of immediate interest due to its known role in the cleavage of other signaling proteins (29) and its implication in Akt signaling (41)(42)(43). Calpains have also been implicated in the regulation of multiple biological processes, including apoptosis, autophagy, proliferation, and migration (28,29,31).…”

Section: Discussionmentioning

confidence: 99%

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Calpain interacts with class IA phosphoinositide 3-kinases regulating their stability and signaling activity

Beltran¹,

Chaussade

Vanhaesebroeck

et al. 2011

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

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Class IA phosphoinositide 3-kinases (PI3Ks) are signaling enzymes with key roles in the regulation of essential cellular functions and disease, including cancer. Accordingly, their activity is tightly controlled in cells to maintain homeostasis. The formation of multiprotein complexes is a ubiquitous mechanism to regulate enzyme activity but the contribution of protein-protein interactions to the regulation of PI3K signaling is not fully understood. We designed an affinity purification quantitative mass spectrometry strategy to identify proteins interacting dynamically with PI3K in response to pathway activation, with the view that such binding partners may have a functional role in pathway regulation. Our study reveals that calpain small subunit 1 interacts with PI3K and that the association between these proteins is lower in cells stimulated with serum compared to starved cells. Calpain and PI3K activity assays confirmed these results, thus demonstrating that active calpain heterodimers associate dynamically with PI3K. In addition, calpains were found to cleave PI3K proteins in vitro (resulting in a reduction of PI3K lipid kinase activity) and to regulate endogenous PI3K protein levels in vivo. Further investigations revealed that calpains have a role in the negative regulation of PI3K/Akt pathway activity (as measured by Akt and ribosomal S6 phosphorylation) and that their inhibition promotes cell survival during serum starvation. These results indicate that the interaction between calpain and PI3K is a novel mechanism for the regulation of class IA PI3K stability and activity.lipid signaling | proteomics | quantitative analysis

show abstract

Calpain small-1 modulates Akt/FoxO3A signaling and apoptosis through PP2A

Cited by 56 publications

References 50 publications

DNA damage response links calpain to cellular senescence

DNA damage response links calpain to cellular senescence

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

Calpain interacts with class IA phosphoinositide 3-kinases regulating their stability and signaling activity

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