Knock-Out of the Neural Death Effector Domain Protein PEA-15 Demonstrates That Its Expression Protects Astrocytes from TNFα-Induced Apoptosis

Kitsberg, Daniel; Formstecher, Étienne; Fauquet, Mireille; Kubeš, Miroslav; Cordier, Jocelyne; Canton, B.; Pan, Guohua; Rolli, Malvyne; Głowiński, J.; Chneiweiss, Hervé

doi:10.1523/jneurosci.19-19-08244.1999

Cited by 141 publications

(152 citation statements)

References 39 publications

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“…This dual effect of Akt has to be correlated to contradictory effects of PEA-15. Indeed, PEA-15 is a strong inhibitor of death receptor-dependent apoptosis (Condorelli et al, 1999;Estelles et al, 1999;Kitsberg et al, 1999) but is associated with decreased cell proliferation (Formstecher et al, 2001;Gaumont-Leclerc et al, 2004). Furthermore, a recent study showed that sustained level of PEA-15 participated in Akt-dependent chemoresistance in human breast cancer cells (Stassi et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…PEA-15 is a small protein abundantly present in brain astrocytes (Araujo et al, 1993) but also widely expressed in other human tissues (Danziger et al, 1995;Estelles et al, 1996;Ramos et al, 1998). PEA-15 regulates multiple cellular functions (Renault et al, 2003), including Ras suppression of integrin activation, and protection against Fas-and tumor necrosis factor ␣-induced apoptosis (Condorelli et al, 1999;Estelles et al, 1999;Kitsberg et al, 1999). Besides, we have already demonstrated that PEA-15 binds to ERK1/2 and prevents their nuclear translocation, which results in blockade of ERK-dependent transcription and cell proliferation in response to serum (Formstecher et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Gervais

Dugourd

Muller

et al. 2006

MBoC

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Angiotensin II (AngII) type 1 receptors (AT1) regulate cell growth through the extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol 3-kinase (PI3K) pathways. ERK1/2 and Akt/protein kinase B, downstream of PI3K, are independently activated but both required for mediating AngII-induced proliferation when expressed at endogenous levels. We investigate the effect of an increase in the expression of wild-type Akt1 by using Chinese hamster ovary (CHO)-AT1 cells. Unexpectedly, Akt overexpression inhibits the AT1-mediated proliferation. This effect could be generated by a cross-talk between the PI3K and ERK1/2 pathways. A functional partner is the phosphoprotein enriched in astrocytes of 15 kDa (PEA-15), an Akt substrate known to bind ERK1/2 and to regulate their nuclear translocation. We report that Akt binds to PEA-15 and that Akt activation leads to PEA-15 stabilization, independently of PEA-15 interaction with ERK1/2. Akt cross-talk with PEA-15 does not affect ERK1/2 activation but decreases their nuclear activity as a result of the blockade of ERK1/2 nuclear accumulation. In response to AngII, PEA-15 overexpression displays the same functional consequences on ERK1/2 signaling as Akt overactivation. Thus, Akt overactivation prevents the nuclear translocation of ERK1/2 and the AngII-induced proliferation through interaction with and stabilization of endogenous PEA-15.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Gervais

Dugourd

Muller

et al. 2006

MBoC

Self Cite

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“…21,22 Decreased levels of PEA-15 protein have been associated with astrocyte protection against TNF-induced apoptosis. 23 In addition to these differentially regulated proteins that have been linked to apoptosis and oxidative stress and are accompanied by morphological correlates, [8][9][10] a dysregulation of proteins associated with cell growth and energy metabolism suggests that these biological processes are also affected by an exposure to high oxygen levels during the brain growth spurt period (Table 1; Figure 2b). …”

Section: Oxidative Stress Apoptosis and Growthmentioning

confidence: 99%

Acute and long-term proteome changes induced by oxidative stress in the developing brain

et al. 2005

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The developing mammalian brain experiences a period of rapid growth during which various otherwise innocuous environmental factors cause widespread apoptotic neuronal death. To gain insight into developmental events influenced by a premature exposure to high oxygen levels and identify proteins engaged in neurodegenerative and reparative processes, we analyzed mouse brain proteome changes at P7, P14 and P35 caused by an exposure to hyperoxia at P6. Changes detected in the brain proteome suggested that hyperoxia leads to oxidative stress and apoptotic neuronal death. These changes were consistent with results of histological and biochemical evaluation of the brains, which revealed widespread apoptotic neuronal death and increased levels of protein carbonyls. Furthermore, we detected changes in proteins involved in synaptic function, cell proliferation and formation of neuronal connections, suggesting interference of oxidative stress with these developmental events. These effects are age-dependent, as they did not occur in mice subjected to hyperoxia in adolescence.

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“…In addition, PEA15 exerts a wide anti-apoptotic action. 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].…”

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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Knock-Out of the Neural Death Effector Domain Protein PEA-15 Demonstrates That Its Expression Protects Astrocytes from TNFα-Induced Apoptosis

Cited by 141 publications

References 39 publications

Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Acute and long-term proteome changes induced by oxidative stress in the developing brain

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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