Publisher Correction: ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism

Boyle, Sarah T.; Poltavets, Valentina; Kular, Jasreen; Pyne, Natasha Theresa; Sandow, Jarrod J.; Lewis, Alexander C.; Murphy, Kendelle J.; Kolesnikoff, Natasha; Moretti, Paul A.B.; Tea, Melinda N; Tergaonkar, Vinay; Timpson, Paul; Pitson, Stuart M.; Webb, Andrew I.; Whitfield, Robert J.; López, Angel F.; Kochetkova, Marina; Samuel, Michael S.

doi:10.1038/s41556-020-0539-3

Cited by 5 publications

(7 citation statements)

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“…A close examination of the functional capacity of DC in vitro showed that although soluble antigen presentation was not affected by PERK inactivation, it induced nevertheless an alteration of IFN-β and cytokines production as well as of DC migratory capacity upon MAMPs activation. Interestingly, ROCK-induced actomyosin contractility in transformed fibroblasts enhances signaling through PERK and ATF4 (Boyle et al, 2020), whereas PERK itself has been shown to interact with filamin-A and to participate to F-Actin remodeling in MEFs (van Vliet et al, 2017), suggesting that the migratory deficit observed in PERK-deficient DCs could be also dependent on these interactions. This finding echoes with the existence of a cross-talk between actin skeleton organization and the main molecular actors involved in the ISR (Chambers et al, 2015;Chen et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Proteostasis in dendritic cells is controlled by the PERK signaling axis independently of ATF4

et al. 2020

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In stressed cells, phosphorylation of eukaryotic initiation factor 2α (eIF2α) controls transcriptome-wide changes in mRNA translation and gene expression known as the integrated stress response. We show here that DCs are characterized by high eIF2α phosphorylation, mostly caused by the activation of the ER kinase PERK (EIF2AK3). Despite high p-eIF2α levels, DCs display active protein synthesis and no signs of a chronic integrated stress response. This biochemical specificity prevents translation arrest and expression of the transcription factor ATF4 during ER-stress induction by the subtilase cytotoxin (SubAB). PERK inactivation, increases globally protein synthesis levels and regulates IFN-β expression, while impairing LPS-stimulated DC migration. Although the loss of PERK activity does not impact DC development, the cross talk existing between actin cytoskeleton dynamics; PERK and eIF2α phosphorylation is likely important to adapt DC homeostasis to the variations imposed by the immune contexts.

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Section: Discussionmentioning

confidence: 99%

Proteostasis in dendritic cells is controlled by the PERK signaling axis independently of ATF4

et al. 2020

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“…5). Interestingly, the protein levels of two UPR-induced genes in the liver, hepcidin 42 and cysteine rich with EGF like domains 2 (CRELD2), an oncogene associated with HCC that promotes survival upon ER stress, [43][44][45][46] were increased in BDD-expressing mpPHH (Fig. 5).…”

Section: Lentiviral Transduction Of Bdd Into Human Primary Hepatocyte...mentioning

confidence: 98%

“…5). Interestingly, the protein levels of two UPR-induced genes in the liver, hepcidin (48) and cysteine rich with EGF like domains 2 (CRELD2), an oncogene associated with HCC that promotes survival upon ER stress (49)(50)(51)(52), were increased in BDD-expressing mpPHH. These results for the first time show that ectopic BDD expression induces ER stress in human hepatocytes.…”

Section: Lentiviral Transduction Of Bdd Into Human Primary Hepatocyte...mentioning

confidence: 99%

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Deng

Kapelanski-Lamoureux

Gao

et al. 2021

Preprint

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Clotting Factor VIII (FVIII) is the protein deficient in hemophilia A (HA), an X chromosome-linked bleeding disorder affecting 24.6 per 100,000 males at birth. Scientists and clinical physicians have been striving hard to find a cure for this disease. Presently, HA therapy involves prophylactic infusion of plasma-derived or recombinant-derived FVIII. Recent clinical studies have reported success using recent adeno-associated-virus (AAV) vector mediated delivery of a FVIII gene. FVIII is a 330 kDa glycoprotein comprised of three domains (A1-A2-B-A3-C1-C2). The B domain is dispensable and B domain-deleted (BDD) FVIII is used in the clinic as an effective protein replacement therapy for HA. Previously, we observed that hydrodynamic tail vein injection of the BDD-FVIII vector resulted in FVIII aggregation and endoplasmic reticulum (ER) stress in murine livers. Additionally, mice that were exposed to transient ER stress and then fed a high fat diet (HFD) for 9 months developed hepatocellular carcinoma (HCC). Therefore, we deduced that ectopic transient expression of FVIII in hepatocytes of mice with subsequent HFD feeding may also develop HCC. Here, we tested hepatocyte expression of two BDD-FVIII variants in vivo. BDD-FVIII aggregates in the ER and induces hepatocyte apoptosis, and N6-FVIII is more efficiently folded and secreted from the ER and causes less hepatocyte apoptosis. We performed tail vein injections of vectors directing expression of BDD-FVIII or N6-BDD to hepatocytes of 6-week old mice. One week after injection, mice were fed 60% HFD for 65 weeks. We found that 50% of mice that received N6-BDD developed liver tumors; in contrast, 90% of mice given BDD-FVIII developed liver tumors. Of the mice injected with BDD-FVIII, 30% developed carcinomas and 60% developed adenomas. Similar masses were not observed in mice that received empty vector. These findings raise concerns about the safety of long-term ectopic expression of FVIII in hepatocytes during FVIII gene therapy

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“…For instance, increased desmoplasia stiffness leads to integrin activation through different tyrosine kinase receptors, such as EGFR, ERBB2, HGFR, and VEGFR, and promotes drug resistance 112 . Other signaling pathways as well as Rho‐associated protein kinase (ROCK), YAP–TAZ, and MAPK cascades can also decrease drug response in different tumor types 113,114 …”

Section: How Ecm Impacts the Development Of Cancer?mentioning

confidence: 99%

“…112 Other signaling pathways as well as Rho-associated protein kinase (ROCK), YAP-TAZ, and MAPK cascades can also decrease drug response in different tumor types. 113,114…”

Section: Intracellular Signalingmentioning

confidence: 99%

An overview of extracellular matrix and its remodeling in the development of cancer and metastasis with a glance at therapeutic approaches

Afshar,

Sanaei,

Ravari

et al. 2023

Cell Biochemistry & Function

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The extracellular matrix (ECM) is an inevitable part of tissues able to provide structural support for cells depending on the purpose of tissues and organs. The dynamic characteristics of ECM let this system fluently interact with the extrinsic triggers and get stiffed, remodeled, and/or degraded ending in maintaining tissue homeostasis. ECM could serve as the platform for cancer progression. The dysregulation of biochemical and biomechanical ECM features might take participate in some pathological conditions such as aging, tissue destruction, fibrosis, and particularly cancer. Tumors can reprogram how ECM remodels by producing factors able to induce protein synthesis, matrix proteinase expression, degradation of the basement membrane, growth signals and proliferation, angiogenesis, and metastasis. Therefore, targeting the ECM components, their secretion, and their interactions with other cells or tumors could be a promising strategy in cancer therapies. The present study initially introduces the physiological functions of ECM and then discusses how tumor‐dependent dysregulation of ECM could facilitate cancer progression and ends with reviewing the novel therapeutic strategies regarding ECM.

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Publisher Correction: ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism

Cited by 5 publications

References 0 publications

Proteostasis in dendritic cells is controlled by the PERK signaling axis independently of ATF4

Proteostasis in dendritic cells is controlled by the PERK signaling axis independently of ATF4

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

An overview of extracellular matrix and its remodeling in the development of cancer and metastasis with a glance at therapeutic approaches

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