Akt up- and down-regulation in response to endoplasmic reticulum stress

Hosoi, Toru; Hyoda, Kanae; Okuma, Yasunobu; Nomura, Yasuyuki; Ozawa, Koichiro

doi:10.1016/j.brainres.2007.03.052

Cited by 87 publications

(71 citation statements)

References 31 publications

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“…The phosphorylation of Akt was, however, only transient, with a peak at 3 to 9 h (55). Consistent with this result, Hosoi et al reported that, in glial cells, Akt phosphorylation was increased by short-term exposure to ER stress but was downregulated by long-term exposure to ER stress inducers (17). These results strongly suggest the potential of ER stress for biphasic, bidirectional regulation of Akt.…”

Section: Discussionsupporting

confidence: 60%

Selective Abrogation of BiP/GRP78 Blunts Activation of NF-κB through the ATF6 Branch of the UPR: Involvement of C/EBPβ and mTOR-Dependent Dephosphorylation of Akt

Nakajima

Hiramatsu

Hayakawa

et al. 2011

Molecular and Cellular Biology

101

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Section: Discussionsupporting

confidence: 60%

Selective Abrogation of BiP/GRP78 Blunts Activation of NF-κB through the ATF6 Branch of the UPR: Involvement of C/EBPβ and mTOR-Dependent Dephosphorylation of Akt

Nakajima

Hiramatsu

Hayakawa

et al. 2011

Molecular and Cellular Biology

101

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“…S5 in the supplementary material), hypoxiainduced ER stress in Pten mutants appeared to act as a mild stressor (Rutkowski et al, 2006) that chondrocytes could ultimately adapt to and survive. Furthermore, an upregulation of p-AKT in chondrocytes may be implicated in protecting cells from ER stressinduced apoptosis (Han et al, 2006;Hosoi et al, 2007;Hu et al, 2007;Matthews et al, 2007;Qu et al, 2004). The activation of HIF1α might also help chondrocytes to survive hypoxia-induced ER stress (Harding et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

PTEN deficiency causes dyschondroplasia in mice by enhanced hypoxia-inducible factor 1α signaling and endoplasmic reticulum stress

Yang¹,

Sun²,

Teng³

et al. 2008

Development

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Chondrocytes within the growth plates acclimatize themselves to a variety of stresses that might otherwise disturb cell fate. The tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10) has been implicated in the maintenance of cell homeostasis. However, the functions of PTEN in regulating chondrocytic adaptation to stresses remain largely unknown. In this study, we have created chondrocyte-specific Pten knockout mice (Pten co/co ;Col2a1-Cre) using the Cre-loxP system. Following AKT activation, Pten mutant mice exhibited dyschondroplasia resembling human enchondroma. Cartilaginous nodules originated from Pten mutant resting chondrocytes that suffered from impaired proliferation and differentiation, and this was coupled with enhanced endoplasmic reticulum (ER) stress. We further found that ER stress in Pten mutant chondrocytes only occurred under hypoxic stress, characterized by an upregulation of unfolded protein response-related genes as well as an engorged and fragmented ER in which collagens were trapped. An upregulation of hypoxia-inducible factor 1α (HIF1α) and downstream targets followed by ER stress induction was also observed in Pten mutant growth plates and in cultured chondrocytes, suggesting that PI3K/AKT signaling modulates chondrocytic adaptation to hypoxic stress via regulation of the HIF1α pathway. These data demonstrate that PTEN function in chondrocytes is essential for their adaptation to stresses and for the inhibition of dyschondroplasia.KEY WORDS: PTEN, Dyschondroplasia, ER stress, HIF1α, Knockout mouse Development 135, 3587-3597 (2008) has been shown to lead to impaired chondrocyte proliferation, differentiation and apoptosis (Oliver et al., 2005;Yang et al., 2005;Yang et al., 2007). A number of studies have shown that deregulation of ER homeostasis is correlated with malformed skeleton development (chondrodysplasia) caused by mutations in genes encoding extracellular matrix (ECM) proteins (Hashimoto et al., 2003;Ho et al., 2007;Pirog-Garcia et al., 2007;Vranka et al., 2001). Chondrocytes expressing a mutant type-X collagen tolerate ER stress, experience delayed terminal differentiation and exhibit chondrodysplasia . A recent study has shown that site-1 protease (S1P; MBTPS1 -Mouse Genome Informatics) is necessary for a specialized ER stress response by chondrocytes that is required for the genesis of normal cartilage (Patra et al., 2007). However, the precise function of the ER stress response in cartilage tumor formation remains largely unknown.The tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10) is a lipid phosphatase, the major substrate of which is phosphatidylinositol 3,4,5-triphosphate (PIP3), a secondary messenger generated by phosphatidylinositol-3-kinase (PI3K). Loss of PTEN function leads to an accumulation of PIP3 and an activation of its downstream effectors, acute transforming retrovirus thymoma [AKT; also known as protein kinase B (PKB) and AKT1]. As a serine/threonine protein kinase, AKT phosphorylates key intermed...

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“…Price et al demonstrated PI3K-mediated signalling pathway promotes chondrocyte survival from ER stress but it does not depend on ERK1/2 activation (Price et al, 2010). Similar reports on the involvement of PI3K/Akt pathway in regulating cell's survival-death decisions in ER stress conditions have been documented (Hyoda et al, 2006;Hosoi et al, 2007). All above reports are studies on UPR induced by pharmacological agents and have not provided data on the relationship between activation of survival pathway and expression of p58 IPK .…”

Section: B Hela Cells Stably Expressing P58mentioning

confidence: 93%

P58^IPKinhibits coxsackievirus-induced apoptosis via the PI3K/Akt pathway requiring activation of ATF6a and subsequent upregulation of mitofusin 2

Zhang

Qiu

et al. 2013

Cell Microbiol

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Summary Previously we found that prolonged endoplasmic reticulum (ER) stress caused by coxsackievirus B3 (CVB3) infection led to p58IPK downregulation and subsequent cell apoptosis. This finding implies that p58 IPK expression benefits cell survival and counteracts CVB3-induced apoptosis. In testing this hypothesis, we first found that PI3K/Akt survival pathway is more sensitive than ERK1/2 in response to p58 IPK expression. This finding was further verified by silencing p58 IPK with specific siRNAs, which led to the significant suppression of phosphorylation of Akt (p-Akt) but not ERK1/2. Further, using CVB3-infected cell line expressing dominant negative ATF6a (DN-ATF6a), we found that expression of p58 IPK and p-Akt was significantly reduced, which led to the decreased cell viability. However, when the DN-ATF6a cells were transiently transfected with p58 IPK , an opposite result was obtained. Finally, by CVB3 infection of cells stably expressing p58 IPK , we found that CVB3-induced mitochondriamediated apoptosis was suppressed, which was evidenced by the reduced cytochrome c release and upregulation of the mitochondrial membrane protein mitofusin 2. However, silencing p58 IPK with either specific siRNAs or DN-ATF6a sensitized cells to CVB3-induced apoptosis. These results suggest that p58 IPK suppresses CVB3-induced apoptosis through selective activation of PI3K/Akt pathway that requires activation of ATF6a and subsequently upregulates mitofusin 2.

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Akt up- and down-regulation in response to endoplasmic reticulum stress

Cited by 87 publications

References 31 publications

Selective Abrogation of BiP/GRP78 Blunts Activation of NF-κB through the ATF6 Branch of the UPR: Involvement of C/EBPβ and mTOR-Dependent Dephosphorylation of Akt

Selective Abrogation of BiP/GRP78 Blunts Activation of NF-κB through the ATF6 Branch of the UPR: Involvement of C/EBPβ and mTOR-Dependent Dephosphorylation of Akt

PTEN deficiency causes dyschondroplasia in mice by enhanced hypoxia-inducible factor 1α signaling and endoplasmic reticulum stress

P58^IPKinhibits coxsackievirus-induced apoptosis via the PI3K/Akt pathway requiring activation of ATF6a and subsequent upregulation of mitofusin 2

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Akt up- and down-regulation in response to endoplasmic reticulum stress

Cited by 87 publications

References 31 publications

Selective Abrogation of BiP/GRP78 Blunts Activation of NF-κB through the ATF6 Branch of the UPR: Involvement of C/EBPβ and mTOR-Dependent Dephosphorylation of Akt

Selective Abrogation of BiP/GRP78 Blunts Activation of NF-κB through the ATF6 Branch of the UPR: Involvement of C/EBPβ and mTOR-Dependent Dephosphorylation of Akt

PTEN deficiency causes dyschondroplasia in mice by enhanced hypoxia-inducible factor 1α signaling and endoplasmic reticulum stress

P58IPKinhibits coxsackievirus-induced apoptosis via the PI3K/Akt pathway requiring activation of ATF6a and subsequent upregulation of mitofusin 2

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P58^IPKinhibits coxsackievirus-induced apoptosis via the PI3K/Akt pathway requiring activation of ATF6a and subsequent upregulation of mitofusin 2