XBP-1, a key regulator of unfolded protein response, activates transcription of IGF1 and Akt phosphorylation in zebrafish embryonic cell line

Hu, Meng-Chuen; Gong, Hong‐Yi; Lin, Gen; Hu, Shao‐Yang; Chen, Mark Hung‐Chih; Huang, Shin-Jie; Liao, Ching-Fong; Wu, Jen‐Leih

doi:10.1016/j.bbrc.2007.05.183

Cited by 59 publications

(43 citation statements)

References 25 publications

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“…ER stress pathways can involve Akt-dependent activation of NF-kB (32) and it has been shown that spliced XBP-1 can activate Akt phosphorylation in a zebrafish embryonic cell line (33). We demonstrated that Akt phosphorylation and IkBa degradation, a hallmark of NF-kB pathway activation, were increased in ZZ monocytes compared with MM monocytes (Fig.…”

Section: Akt Is Phosphorylated and Ikba Degraded In Monocytes From Zzsupporting

confidence: 50%

Evidence for Unfolded Protein Response Activation in Monocytes from Individuals with α-1 Antitrypsin Deficiency

Carroll

Greene

O’Connor

et al. 2010

The Journal of Immunology

105

101

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The hereditary disorder α-1 antitrypsin (AAT) deficiency results from mutations in the SERPINA1 gene and presents with emphysema in young adults and liver disease in childhood. The most common form of AAT deficiency occurs because of the Z mutation, causing the protein to fold aberrantly and accumulate in the endoplasmic reticulum (ER). This leads to ER stress and contributes significantly to the liver disease associated with the condition. In addition to hepatocytes, AAT is also synthesized by monocytes, neutrophils, and epithelial cells. In this study we show for the first time that the unfolded protein response (UPR) is activated in quiescent monocytes from ZZ individuals. Activating transcription factor 4, X-box binding protein 1, and a subset of genes involved in the UPR are increased in monocytes from ZZ compared with MM individuals. This contributes to an inflammatory phenotype with ZZ monocytes exhibiting enhanced cytokine production and activation of the NF-κB pathway when compared with MM monocytes. In addition, we demonstrate intracellular accumulation of AAT within the ER of ZZ monocytes. These are the first data showing that Z AAT protein accumulation induces UPR activation in peripheral blood monocytes. These findings change the current paradigm regarding lung inflammation in AAT deficiency, which up until now was derived from the protease–anti-protease hypothesis, but which now must include the exaggerated inflammatory response generated by accumulated aberrantly folded AAT in circulating blood cells.

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Section: Akt Is Phosphorylated and Ikba Degraded In Monocytes From Zzsupporting

confidence: 50%

Evidence for Unfolded Protein Response Activation in Monocytes from Individuals with α-1 Antitrypsin Deficiency

Carroll

Greene

O’Connor

et al. 2010

The Journal of Immunology

105

101

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“…In support of this conclusion, XBP1-deficient cells have reduced AKT phosphorylation without changes in PTEN expression compared with JunB KD cells. XBP1 has been shown to modulate AKT activity in other cell types, 31,42 and XBP1 may directly bind PI3K, facilitating AKT phosphorylation in endothelial cells. 43 JunB may also modulate AKT phosphorylation through a XBP1-dependent improvement of the ER folding capacity and consequent restoration of mTOR or via inhibition of protein phosphatase 2A, two important pathways previously shown to regulate AKT.…”

Section: Discussionmentioning

confidence: 99%

JunB protects β-cells from lipotoxicity via the XBP1–AKT pathway

et al. 2014

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Diets rich in saturated fats may contribute to the loss of pancreatic b-cells in type 2 diabetes. JunB, a member of the activating protein 1 (AP-1) transcription factor family, promotes b-cell survival and mediates part of the beneficial effects of GLP-1 agonists. In this study we interrogated the molecular mechanisms involved in JunB-mediated b-cell protection from lipotoxicity. The saturated fatty acid palmitate decreased JunB expression, and this loss may contribute to b-cell apoptosis, as overexpression of JunB protected cells from lipotoxicity. Array analysis of JunB-deficient b-cells identified a gene expression signature of a downregulated endoplasmic reticulum (ER) stress response and inhibited AKT signaling. JunB stimulates XBP1 expression via the transcription factor c/EBPd during ER stress, and forced expression of XBP1s rescued the viability of JunB-deficient cells, constituting an important antiapoptotic mechanism. JunB silencing inhibited AKT activation and activated the proapoptotic Bcl-2 protein BAD via its dephosphorylation. BAD knockdown reversed lipotoxic b-cell death potentiated by JunB siRNA. Interestingly, XBP1s links JunB and AKT signaling as XBP1 knockdown also reduced AKT phosphorylation. GLP-1 agonists induced cAMP-dependent AKT phosphorylation leading to b-cell protection against palmitate-induced apoptosis. JunB and XBP1 knockdown or IRE1 inhibition decreased AKT activation by cAMP, leading to b-cell apoptosis. In conclusion, JunB modulates the b-cell ER stress response and AKT signaling via the induction of XBP1s. The activation of the JunB gene network and the crosstalk between the ER stress and AKT pathway constitute a crucial defense mechanism by which GLP-1 agonists protect against lipotoxic b-cell death. These findings elucidate novel b-cell-protective signal transduction in type 2 diabetes.

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“…24 It can also activate Akt to mediate anti-apoptotic signals. 25 On the other hand, the kinase domain of IRE1 is capable of autophosphorylation, with subsequent downstream activation of cJun N-terminal kinase (JNK). 26 It is this activity of IRE1 that links it to other protein degradation pathways within the cell, such as the autophagy pathway, as JNK phosphorylates Bcl2, allowing the essential autophagy gene, Beclin1, to associate with phosphatidylinositol-3-kinase (PI3K) Class III to trigger autophagy (Figure 1).…”

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confidence: 99%

DangER: protein ovERload. Targeting protein degradation to treat myeloma

Aronson¹,

Davies²

2012

Haematologica

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Myeloma is a malignancy of the antibody-producing plasma cells and, as such, these cells synthesize large quantities of unfolded or misfolded immunoglobulin. The build-up of excess protein triggers a number of downstream signal transduction cascades, including endoplasmic reticulum stress and autophagy. As a result, myeloma cells are uniquely reliant on these and other protein handling pathways for their survival. Strategies aimed at targeting this vulnerability have proved successful with the proteasome inhibitor, bortezomib, already licensed for clinical use. In addition to the proteasome, various other points within the protein handling pathways are also the subject of drug discovery projects, with some already progressing into clinical trials. These include compounds directed against heat shock proteins, the unfolded protein response and pathways both upstream and downstream of the proteasome.More recently, the role of autophagy has been recognized in myeloma. In this review, we discuss the various pathways used by myeloma cells for survival, with particular emphasis on the emerging role and conundrum of autophagy, as well as highlighting pre-clinical research on novel inhibitors targeting protein handling pathways.Key words: autophagy, proteasome, ER stress, heat-shock chaperones, unfolded protein response.Citation: Aronson LI and Davies FE. DangER: protein ovERload. Targeting protein degradation to treat myeloma. Haematologica 2012;97(8):1119-1130. doi:10.3324/haematol.2012 This is an open-access paper. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nbeen extensively reviewed and so will not be covered further here. 7,8 We aim to provide an overview of the protein handling and stress response pathways. We highlight the potential points in these pathways that can be targeted therapeutically, and review the supporting pre-clinical data. Protein handling pathwaysUnder normal conditions, the synthesis, folding and degradation of cellular proteins are balanced processes. In myeloma cells, however, the protein folding capacity of the endoplasmic reticulum (ER) is overloaded by large quantities of immunoglobulin and cells must adapt to this continual stress. 9 A close relationship with common signaling nodes therefore exists between the ubiquitin proteasome pathway, cellular stress pathways such as the unfolded protein response (UPR), heat shock response and autophagy. Ubiquitin proteasome pathwayThe main cellular pathway for the removal and destruction of proteins is the ubiquitin proteasome pathway. This involves the sequential enzymatic transfer of ubiquitin monomers onto an elongating polyubiquitin chain bound at the lysine 11 or lysine 48 residues of target proteins. 10 In the first step of this cascade, an E1 activating enzyme, typically ubiquitin activating enzyme (UAE, also known as UBA1), binds ubiquitin. A second ubiquitin monomer binds to a different site on the E1 enzyme and the first ubiquitin is transferred to an E2 ubiquitin-conjugating enzyme. The final step involves the transfer of ubiq...

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XBP-1, a key regulator of unfolded protein response, activates transcription of IGF1 and Akt phosphorylation in zebrafish embryonic cell line

Cited by 59 publications

References 25 publications

Evidence for Unfolded Protein Response Activation in Monocytes from Individuals with α-1 Antitrypsin Deficiency

Evidence for Unfolded Protein Response Activation in Monocytes from Individuals with α-1 Antitrypsin Deficiency

JunB protects β-cells from lipotoxicity via the XBP1–AKT pathway

DangER: protein ovERload. Targeting protein degradation to treat myeloma

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