Emerging Roles of the Endoplasmic Reticulum Associated Unfolded Protein Response in Cancer Cell Migration and Invasion

Limia, Celia M.; Sauzay, Chloé; Urra, Hery; Hetz, Claudio; Chevet, Éric; Avril, Tony

doi:10.3390/cancers11050631

Cited by 69 publications

(57 citation statements)

References 205 publications

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“…One downstream effect of ER stress following intrinsic or extrinsic challenge is the regulation of processes involved in the remodeling of the extracellular matrix 18,19 . Therefore, we sought to examine the transcriptional levels of MMP9, a matrix metalloprotease involved in the degradation of denatured collagens, including basement membrane type IV and anchoring fibril type VII collagens.…”

Section: Resultsmentioning

confidence: 99%

Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the ocular surface

Woodward

Zazzo

Bombardieri

et al. 2020

Sci Rep

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A growing body of evidence implicates endoplasmic reticulum (eR) stress in the pathogenesis of chronic inflammatory and autoimmune disorders. Here, we demonstrate that the proinflammatory cytokine tnfα stimulates matrix metalloproteinase 9 (MMP9) at the ocular surface through a c-Fosdependent mechanism of eR stress. We found positive reactivity of the molecular chaperone Bip/ GRP78 in conjunctival epithelium of patients with ocular cicatricial pemphigoid and increased levels of BiP/GRP78, sXBP1 and GRP94 in human corneal epithelial cells treated with TNFα. pharmacological blockade of eR stress in vitro using dexamethasone or the chemical chaperones TUDCA and 4PBA attenuated MMP9 expression and secretion in the presence of TNFα. Moreover, expression analysis of genes associated with inflammation and autoimmunity identified the c-Fos proto-oncogene as a mediator of eR stress responses in epithelial cells. Substantially less tnfα-induced MMP9 expression occurred when c-Fos signaling was suppressed with a function-blocking antibody. Taken together, these results indicate that activation of ER stress contributes to promote inflammation-mediated proteolytic activity and uncovers a target for restoring tissue homeostasis in ocular autoimmune disease.

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Section: Resultsmentioning

confidence: 99%

Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the ocular surface

Woodward

Zazzo

Bombardieri

et al. 2020

Sci Rep

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“…Unfolded protein response components inhibit general protein translation and trigger the expression of ER‐resident chaperones and proteases required to resolve protein folding deficits. Failure of the UPR to re‐establish proteostasis leads to the induction of ER stress‐induced cell death . The UPR consists of three main pathways with partially overlapping functions: PERK (protein kinase RNA‐like endoplasmic reticulum kinase), IRE1, and ATF6.…”

Section: Introductionmentioning

confidence: 99%

The active nuclear form of SREBP1 amplifies ER stress and autophagy via regulation of PERK

Mao

Liu

et al. 2019

The FEBS Journal

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Endoplasmic reticulum (ER) stress and autophagy dysfunction contribute to the establishment and progression of diverse pathologies. Proteolytic activation of the transcription factor nSREBP1 is induced under ER stress; however, little is known about how SREBP1 and its nuclear active form nSREBP1 influence autophagy and unfolded protein response (UPR) activation in osteosarcoma cells. Our research focused on the effect of SREBP1/nSREBP1 upon apoptosis and autophagy during ER stress and the molecular mechanisms involved. Here, we showed that nSREBP1 binds to the promoter of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and then regulates ER stress, cell growth, cell apoptosis, and autophagy through the PERK signaling pathway. nSREBP1 increased PERK gene expression and phosphorylation. nSREBP1 was further demonstrated to activate ER stress response through stimulatory effects on PERK signaling. Overexpression of SREBP1 increased its cleavage and release of nSREBP1; therefore, the effect of SREBP1 is achieved through the enhancement of the expression of nSREBP1. Overexpression of SREBP1/nSREBP1 amplifies PERK-associated cell cycle stagnation with G1 phase arresting, S phase reducing, and G2-M phase delaying. LV-SREBP1/nSREBP1 can also bolster PERK's ER stress-associated proapoptotic effects. LV-SREBP1/nSREBP1 and LV-PERK can activate autophagy in ER stress response, along with the overexpression of SREBP1/nSREBP1 and PERK. This resulted in amplification of PERK-related changes to cell proliferation and ER stress-mediated apoptosis and autophagy, with the biological effect of nSREBP1 relying on PERK, which makes up one of the three branches of the UPR signaling pathway. This study reveals important roles for SREBP1/nSREBP1 in PERK signaling under ER stress. Furthermore, nSREBP1, the nuclear active form of SREBP1, is able to robustly augment the effects of PERK. Description of the link between PERK and SREBP1/nSREBP1 function offers an improved understanding of the ER stress response and insight into the biological function of SREBP1/nSREBP1. Abbreviations ATF4, activating transcription factor-4; CHOP, C/EBP-homologous protein; eIF2a, eukaryotic translation initiation factor-2a; ERAD, endoplasmic reticulum-associated protein degradation; ERS, endoplasmic reticulum stress; INSIG1, insulin-induced gene 1; PERK, protein kinase RNA-like endoplasmic reticulum kinase; SCAP, SREBP cleavage-activating protein; SRE, sterol regulatory element; SREBPs, sterol regulatory element-binding proteins; UPR, unfolded protein response.

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“…The UPR is classically described as an adaptive three-branched pathway that aims to restore the balance between newly synthesized and mature proteins and has been extensively reviewed within this special issue and elsewhere [33,[35][36][37]. The three branches of the canonical UPR pathway are represented by three transmembrane proximal sensors: inositol-requiring enzyme 1α (IRE1α) and IRE1β, protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (both α and β isoforms and referred to as ATF6) [35][36][37]. In normal conditions, their activity is blocked by binding of their luminal domains to the heat-shock ER resident chaperone Glucose-regulated protein 78/Binding immunoglobulin protein GRP78/BiP and other associated factors [36,37].…”

Section: Stress To the Endoplasmic Reticulum Triggers The Unfolded Prmentioning

confidence: 99%

“…The three branches of the canonical UPR pathway are represented by three transmembrane proximal sensors: inositol-requiring enzyme 1α (IRE1α) and IRE1β, protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (both α and β isoforms and referred to as ATF6) [35][36][37]. In normal conditions, their activity is blocked by binding of their luminal domains to the heat-shock ER resident chaperone Glucose-regulated protein 78/Binding immunoglobulin protein GRP78/BiP and other associated factors [36,37]. Triggering of the UPR releases the ER stress sensors from BiP, leading to their activation and recovery of protein folding capacity [36,38].…”

Section: Stress To the Endoplasmic Reticulum Triggers The Unfolded Prmentioning

confidence: 99%

“…In normal conditions, their activity is blocked by binding of their luminal domains to the heat-shock ER resident chaperone Glucose-regulated protein 78/Binding immunoglobulin protein GRP78/BiP and other associated factors [36,37]. Triggering of the UPR releases the ER stress sensors from BiP, leading to their activation and recovery of protein folding capacity [36,38]. This includes a general down-regulation of protein synthesis and stimulation of ER-associated degradation of misfolded proteins (ERAD).…”

Section: Stress To the Endoplasmic Reticulum Triggers The Unfolded Prmentioning

confidence: 99%

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Alternative Mechanisms of p53 Action During the Unfolded Protein Response

Fusee

Marı́n

Fåhræus

et al. 2020

Cancers

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The tumor suppressor protein p53 orchestrates cellular responses to a vast number of stresses, with DNA damage and oncogenic activation being some of the best described. The capacity of p53 to control cellular events such as cell cycle progression, DNA repair, and apoptosis, to mention some, has been mostly linked to its role as a transcription factor. However, how p53 integrates different signaling cascades to promote a particular pathway remains an open question. One way to broaden its capacity to respond to different stimuli is by the expression of isoforms that can modulate the activities of the full-length protein. One of these isoforms is p47 (p53/47, ∆40p53, p53∆N40), an alternative translation initiation variant whose expression is specifically induced by the PERK kinase during the Unfolded Protein Response (UPR) following Endoplasmic Reticulum stress. Despite the increasing knowledge on the p53 pathway, its activity when the translation machinery is globally suppressed during the UPR remains poorly understood. Here, we focus on the expression of p47 and we propose that the alternative initiation of p53 mRNA translation offers a unique condition-dependent mechanism to differentiate p53 activity to control cell homeostasis during the UPR. We also discuss how the manipulation of these processes may influence cancer cell physiology in light of therapeutic approaches.Cancers 2020, 12, 401 2 of 17 carcinomas, and leukemia, particularly in children and young adults [6]. Patients with this syndrome generally express both the mutant and wild-type (p53wt) forms of p53 in all tissues. During cancer progression, the wild-type activity of the protein is often lost, either due to the occurrence of dominant-negative (DNE) inhibitor mutations, to a gain of function (GOF) mutation that favors cancer progression, or to a direct loss of p53wt allele, a phenomenon known as loss of heterozygosity (LOH) [1,6]. The important handicap imposed by expressing half of the normal amount of fully active p53 in Li-Fraumeni patients [1,7] highlights the sensitivity of the pathway to small changes in p53 levels.In tumor cells containing wild-type TP53 gene, p53 activity might be compromised through different mechanisms. A well-known example constitutes the inhibitory interaction of p53 with proteins from cancer-associated virus, such as the T antigen from SV40 [8,9], adenovirus E1b protein [10] and the E6 protein from human papilloma virus (HPV) types 16 and 18 [11,12]. Overexpression of cellular regulators such as Mouse double minute 2 homolog MDM2 [13] and its homolog MDMX (MDM4) [14] can also suppress p53 activity and therefore have oncogenic potential. Under normal conditions, MDM2 and MDMX bind the conserved BOX-I motif in the N-terminus of p53 and mask its transactivation (TA) domain [13][14][15][16]. Moreover, MDM2, but not MDMX, possesses an E3-ubiquitin ligase activity that relies on its C-terminal RING domain, and targets p53 for 26S-dependent proteasomal degradation [17].p53 activation during the DNA damage response (DDR) has...

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Emerging Roles of the Endoplasmic Reticulum Associated Unfolded Protein Response in Cancer Cell Migration and Invasion

Cited by 69 publications

References 205 publications

Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the ocular surface

Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the ocular surface

The active nuclear form of SREBP1 amplifies ER stress and autophagy via regulation of PERK

Alternative Mechanisms of p53 Action During the Unfolded Protein Response

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