Omi/HtrA2 Promotes Cell Death by Binding and Degrading the Anti-apoptotic Protein ped/pea-15

Trencia, Alessandra; Fiory, Francesca; Maitan, Maria Alessandra; Vito, Pasquale; Barbagallo, Alessia P.M.; Perfetti, Anna; Miele, Claudia; Ungaro, Paola; Oriente, Francesco; Cilenti, Lucia; Zervos, Antonis S.; Formisano, Pietro; Béguinot, Francesco

doi:10.1074/jbc.m406317200

Cited by 77 publications

(70 citation statements)

References 32 publications

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“…Protease activity of Omi is not necessarily required for cell death It has been reported that the protease activity of Omi, at least in part, contributes to cell death execution (Yang et al, 2003;Cilenti et al, 2004;Trencia et al, 2004). We found that WTS can promote the protease activity of Omi to induce cell death (Kuninaka et al, 2005).…”

Section: Proteolysis Of Warts By Omi Protease S Kuninaka Et Almentioning

confidence: 61%

“…Based on those findings, Omi is being considered to act on maintenance of mitochondrial homeostasis. Collectively, protease activity is important for Omi to function properly in vivo, however, substrates reported to date are all involved in the apoptotic property of Omi (Yang et al, 2003;Cilenti et al, 2004;Trencia et al, 2004). Therefore, identification of non-apoptotic substrates of Omi is required to elucidate its physiological functions.…”

Section: Introductionmentioning

confidence: 99%

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Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

et al. 2006

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The serine protease Omi/HtrA2 was initially regarded as a proapoptotic molecule that proteolyses several proteins to induce cell death. Recent studies, however, indicate that loss of Omi protease activity increases susceptibility to stress-induced cell death. These complicated findings suggest that the protease activity of Omi is involved not only in apoptosis but also in cellular homeostasis. However, the targets which Omi uses to mediate this novel process are unknown. Previously, we showed that WARTS (WTS)/large tumor-suppressor 1 mitotic kinase interacts with the protein/discs-large protein/zonula (PDZ) domain of Omi and promotes its protease activity. We now report that WTS is a substrate for Omi protease activity, thus it is not only a regulator but also a downstream target of this protease. Interaction with Omi PDZ domain is required for WTS to be proteolysed. When caspase-9-deficient mouse embryonic fibroblasts (MEFs) were treated with staurosporine, WTS was proteolysed by activated endogenous Omi without induction of cell death. Therefore, protease activity of Omi and proteolysis of WTS are not necessarily required for cell death. We found that depletion of Omi from HeLa cells results in accelerated cell proliferation despite no significant change in the duration of mitosis. The depletion of WTS showed the same effect on S phase progression. Therefore, WTS proteolytic fragment(s) generated by Omi may act as an inhibitor of G1/S progression. Our data reveal a role for Omi-mediated processing of WTS in negative regulation of cell cycle progression at interphase, suggesting a novel function of Omi other than apoptosis.

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Section: Proteolysis Of Warts By Omi Protease S Kuninaka Et Almentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

et al. 2006

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“…Unlike the case of Pifithrin-a treatment, the forced expression of Bcl-2 in nucleostemin null ES cells to inhibit caspase-dependent apoptosis did not lead to even partial recovery of cell viability, implying that caspase-independent pathways also contributed significantly to the death of ES cells. A number of reports have described caspase-independent cell death, including induction by HtrA2/Omi [46] or apoptosis inducing factor [47]. However, it appears that the different types of caspaseindependent cell death do not share an underlying cause, except for the fact that the detrimental phenomena cannot be prevented by pharmacological or genetic inactivation of caspases [48,49].…”

Section: Discussionmentioning

confidence: 99%

Differential Requirement for Nucleostemin in Embryonic Stem Cell and Neural Stem Cell Viability

et al. 2009

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Stem cells have the remarkable ability to self-renew and to generate multiple cell types. Nucleostemin is one of proteins that are enriched in many types of stem cells. Targeted deletion of nucleostemin in the mouse results in developmental arrest at the implantation stage, indicating that nucleostemin is crucial for early embryogenesis. However, the molecular basis of nucleostemin function in early mouse embryos remains largely unknown, and the role of nucleostemin in tissue stem cells has not been examined by gene targeting analyses due to the early embryonic lethality of nucleostemin null animals. To address these questions, we generated inducible nucleostemin null embryonic stem (ES) cells in which both alleles of nucleostemin are disrupted, but nucleostemin cDNA under the control of a tetracycline-responsive transcriptional activator is introduced into the Rosa26 locus. We show that loss of nucleostemin results in reduced cell proliferation and increased apoptosis in both ES cells and ES cell-derived neural stem/progenitor cells. The reduction in cell viability is much more profound in ES cells than in neural stem/progenitor cells, an effect that is mediated at least in part by increased induction and accumulation of p53 and/or activated caspase-3 in ES cells than in neural stem/progenitor cells.

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“…Consistent with this possibility, recent studies by Data are presented as the means ± SEM or %. Statistical significance was assessed by comparing all three groups of subjects our own as well as other laboratories have shown that PEA15 is highly regulated at the post-translational level [1,2,7,12]. Previous studies in cultured cells and in transgenic mice have shown that overexpression of the gene encoding PEA15 determines resistance to insulin action and impairs glucose-induced insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

“…It binds Fas-associated death domain (FADD) and caspase-8, thereby protecting against cytokine-induced apoptosis [9][10][11]. PEA15 also binds to Omi/HtrA2 to inhibit apoptosis triggered by stress and physical agents [12]. Importantly, there is evidence indicating that PEA15 anti-apoptotic action has an important role in the development and progression of certain cancers in humans as well as in rodents [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

The PEA15 gene is overexpressed and related to insulin resistance in healthy first-degree relatives of patients with type 2 diabetes

et al. 2006

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Aims/hypothesis Overexpression of the gene encoding phosphoprotein enriched in astrocytes 15 (PEA15), also known as phosphoprotein enriched in diabetes (PED), causes insulin resistance and diabetes in transgenic mice and has been observed in type 2 diabetic individuals. The aim of this study was to investigate whether PEA15 overexpression occurs in individuals at high risk of diabetes and whether it is associated with specific type 2 diabetes subphenotypes. Subjects and methods We analysed PEA15 expression in euglycaemic first-degree relatives (FDR) of type 2 diabetic subjects.Results The expression of PEA15 in peripheral blood leucocytes (PBLs) paralleled that in fat and skeletal muscle tissues. In PBLs from the FDR, PEA15 expression was two-fold higher than in euglycaemic individuals with no family history of diabetes (control subjects), both at the protein and the mRNA level (p<0.001). The expression of PEA15 was comparable in FDR and type 2 diabetic subjects and in each group close to one-third of the subjects expressed PEA15 levels more than 2 SD higher than the mean of control subjects. Subjects with IFG with at least one type 2 diabetes-affected FDR also overexpressed PEA15 (p<0.05). In all the groups analysed, PEA15 expression was independent of sex and unrelated to age, BMI, waist circumference, systolic and diastolic BP, and fasting cholesterol, triacylglycerol and glucose levels. However, in euglycaemic FDR of type 2 diabetic subjects, PEA15 expression was inversely correlated with insulin sensitivity (r=−557, p=0.01). Conclusions/interpretation We conclude that PEA15 overexpression represents a common defect in FDR of patients with type 2 diabetes and is correlated with reduced insulin sensitivity in these individuals.

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Omi/HtrA2 Promotes Cell Death by Binding and Degrading the Anti-apoptotic Protein ped/pea-15

Cited by 77 publications

References 32 publications

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

Differential Requirement for Nucleostemin in Embryonic Stem Cell and Neural Stem Cell Viability

The PEA15 gene is overexpressed and related to insulin resistance in healthy first-degree relatives of patients with type 2 diabetes

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