PERK-dependent regulation of IAP translation during ER stress

Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
Oncogene (Impact Factor: 8.46). 12/2008; 28(6):910-20. DOI: 10.1038/onc.2008.428
Source: PubMed


Exposure of cells to endoplasmic reticulum (ER) stress leads to activation of phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway and transcriptional induction of the inhibitor of apoptosis family of proteins. One of the proximal effectors of the ER stress response, the PKR-like ER kinase (PERK), leads to cellular adaptation to stress by multiple mechanisms, including attenuation of protein synthesis and transcriptional induction of pro-survival genes. Although PERK activity leads to cellular adaptation to ER stress, we now demonstrate that PERK activity also inhibits the ER stress-induced apoptotic program through the induction of cellular inhibitor of apoptosis (cIAP1 and cIAP2) proteins. This induction of IAPs occurs through both transcriptional and translational responses that are PERK dependent. Reintroduction of cIAP1 or cIAP2 expression into PERK-/- murine embryonic fibroblasts during ER stress delays the early onset of ER stress-induced caspase activation and apoptosis observed in these cells. Furthermore, we demonstrate that the activation of the PI3K-Akt pathway by ER stress is dependent on PERK, suggesting additional ways in which PERK activity protects cells from ER stress-induced apoptosis.

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Available from: Robert B Hamanaka, Jan 08, 2014
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    • "CHOP promotes ER stress-induced apoptosis [26] while GADD34 is involved in a negative feedback loop to counteract PERK by dephosphorylation of eIF2α, which resumes protein synthesis and sensitize cells to apoptosis [27]. Interesting, PERK also inhibits ER stress-induced apoptosis via induction of cIAPs (cellular inhibitors of apoptosis proteins) [28], and is a critical crosstalk regulator to influence the entire UPR in determining cell fate under ER stress [29]. In addition, another study has shown that activation of PERK could lead to down-regulation of anti-apoptosis protein XIAP, which could lead to increase in apoptosis [30]. "
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    ABSTRACT: Stress pathways monitor intracellular systems and deploy a range of regulatory mechanisms in response to stress. One of the best-characterized pathways, the unfolded protein response (UPR), is an intracellular signal transduction pathway that monitors endoplasmic reticulum (ER) homeostasis. Its activation is required to alleviate the effects of ER stress and is highly conserved from yeast to human. Although metazoans have three UPR outputs, yeast cells rely exclusively on the inositol-requiring enzyme-1 (Ire1) pathway, which is conserved in all Eukaryotes. In general, the UPR program activates hundreds of genes to alleviate ER stress but it can lead to apoptosis if the system fails to restore homeostasis. In this review, we summarize the major advances in understanding the response to ER stress in S. cerevisiae, S. pombe, and humans. The contribution of solved protein structures to a better understanding of the UPR pathway is discussed. Finally, we cover the interplay of ER stress in the development of diseases.
    Full-text · Article · Jun 2014 · Bioscience Reports
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    • "As you can see in Fig. 1A, wogonin (100 µm) induced strong CRT cell surface translocation in MFC cancer cells in as detected by Western blots testing cell surface CRT. Among the signal pathways that regulates CRT translocation and corresponding immunogenic cell death/apoptosis, it is now well established that pre-apoptotic ER stress and the phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) and the upstream signal kinase protein kinase R-like endoplasmic reticulum kinase (PERK) are the main ones [13]. The phosphorylation of the eIF2α by the PERK anterograde transport of CRT from the ER to the Golgi apparatus and exocytosis of CRT-containing vesicles, finally results in CRT translocation onto the plasma membrane surface, which serves as key “eat-me” signal [1], [4], [14]–[17]. "
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    ABSTRACT: In response to ionizing irradiation and certain chemotherapeutic agents, dying tumor cells elicit a potent anticancer immune response. However, the potential effect of wogonin (5,7-dihydroxy-8-methoxyflavone) on cancer immunogenicity has not been studied. Here we demonstrated for the first time that wogonin elicits a potent antitumor immunity effect by inducing the translocation of calreticulin (CRT) and Annexin A1 to cell plasma membrane as well as the release of high-mobility group protein 1 (HMGB1) and ATP. Signal pathways involved in this process were studied. We found that wogonin-induced reactive oxygen species (ROS) production causes an endoplasmic reticulum (ER) stress response, including the phosphorylation of PERK (PKR-like endoplasmic reticulum kinase)/PKR (protein kinase R) and eIF2α (eukaryotic initiation factor 2α), which served as upstream signal for the activation of phosphoinositide 3-kinase (PI3K)/AKT, inducing calreticulin (CRT)/Annexin A1 cell membrane translocation. P22/CHP, a Ca(2+)-binding protein, was associated with CRT and was required for CRT translocation to cell membrane. The releases of HMGB1 and ATP from wogonin treated MFC cells, alone or together with other possible factors, activated dendritic cells and induced cytokine releases. In vivo study confirmed that immunization with wogonin-pretreated tumor cells vaccination significantly inhibited homoplastic grafted gastric tumor growth in mice and a possible inflammatory response was involved. In conclusion, the activation of PI3K pathway elicited by ER stress induced CRT/Annexin A1 translocation ("eat me" signal) and HMGB1 release, mediating wogonin-induced immunity of tumor cell vaccine. This indicated that wogonin is a novel effective candidate of immunotherapy against gastric tumor.
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    • "True to its name, the cIAPs play an important role in the inhibition of apoptosis. They are induced to promote survival during cellular stresses such as detachment from extracellular matrix [22] and ER stress [23]. They are also induced by prosurvival signaling such as nuclear factor (NF)-κB [24] [25]. "
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    ABSTRACT: Cellular inhibitors of apoptosis proteins 1 and 2 (cIAP1/2) are members of the inhibitor of apoptosis protein (IAP) family that has been implicated in the pathology of human cancers due to their overexpression and function as blockers of cell death in various cancers. As a result, small molecule IAP antagonists have been developed and are currently under clinical evaluation for potential therapeutic use. In contrast, recent evidence has indicated a tumour-suppressing role for the cIAPs. Mutations in or loss of cIAPs have been identified as molecular lesions that contribute to constitutive activation of NF-κB in hematopoietic malignancies. These studies reveal a context-dependent role for the cIAPs wherein both their overexpression and loss may contribute to tumourigenesis.
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