scholarly journals Hypoxia-induced SETX links replication stress with the unfolded protein response

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shaliny Ramachandran ◽  
Tiffany S. Ma ◽  
Jon Griffin ◽  
Natalie Ng ◽  
Iosifina P. Foskolou ◽  
...  
Keyword(s):  
Dna Damage ◽  
Unfolded Protein Response ◽  
Cellular Response ◽  
Replication Stress ◽  
Therapy Resistance ◽  
Dna Helicase ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response

AbstractTumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. Therefore, suggesting that, SETX plays a role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.

scholarly journals Hypoxia-induced SETX links replication stress with the unfolded protein response

2020 ◽  
Author(s):  
Shaliny Ramachandran ◽  
Tiffany Ma ◽  
Natalie Ng ◽  
Iosifina P. Foskolou ◽  
Ming-Shih Hwang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Unfolded Protein Response ◽  
Cellular Response ◽  
Biological Response ◽  
Transcriptional Response ◽  
Replication Stress ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response

ABSTRACTThe levels of hypoxia associated with resistance to radiotherapy significantly impact cancer patient prognosis. These levels of hypoxia initiate a unique transcriptional response with the rapid activation of numerous transcription factors in a background of global repression of transcription. Here, we show that the biological response to radiobiological hypoxia includes the induction of the DNA/RNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. SETX plays a key role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we show that the mechanism of SETX induction is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to radiobiological hypoxia, which includes both a replication stress dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.

scholarly journals HSP-4/BiP expression in secretory cells is regulated by a lineage-dependent differentiation program and not by the unfolded protein response

2018 ◽  
Author(s):  
Ji Zha ◽  
Jasmine Alexander-Floyd ◽  
Tali Gidalevitz
Keyword(s):  
Unfolded Protein Response ◽  
Secretory Cells ◽  
C Elegans ◽  
Unfolded Protein ◽  
Daughter Cells ◽  
Developmental Program ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response ◽  
Anticipatory Activation

AbstractDifferentiation of secretory cells leads to sharp increases in protein synthesis, challenging ER proteostasis. Anticipatory activation of the unfolded protein response (UPR) prepares cells for the onset of secretory function by expanding the ER size and folding capacity. How cells ensure that the repertoire of induced chaperones matches their post-differentiation folding needs is not well understood. We find that during differentiation of stem-like seam cells, a typical UPR target, the C. elegans BiP homologue HSP-4, is selectively induced in alae-secreting daughter cells, but is repressed in hypodermal daughter cells. Surprisingly, this lineage-dependent induction bypasses the requirement for UPR signaling, and instead is controlled by a specific developmental program. The repression of HSP-4 in hypodermal-fated cells requires a transcriptional regulator BLMP-1/BLIMP1, involved in differentiation of mammalian secretory cells. The HSP-4 induction is anticipatory, and is required for the integrity of secreted alae. Thus, differentiation programs can directly control a broad-specificity chaperone that is normally stress-dependent, to ensure the integrity of secreted proteins.

scholarly journals The Unfolded Protein Response in Breast Cancer

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 344 ◽  
Author(s):  
Eoghan McGrath ◽  
Susan Logue ◽  
Katarzyna Mnich ◽  
Shane Deegan ◽  
Richard Jäger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Unfolded Protein Response ◽  
Therapy Resistance ◽  
Breast Cancers ◽  
Unfolded Protein ◽  
Promising Target ◽  
A Cell ◽  
The Unfolded Protein Response ◽  
Cell Stress Response ◽  
Protein Response

In 2018, in the US alone, it is estimated that 268,670 people will be diagnosed with breast cancer, and that 41,400 will die from it. Since breast cancers often become resistant to therapies, and certain breast cancers lack therapeutic targets, new approaches are urgently required. A cell-stress response pathway, the unfolded protein response (UPR), has emerged as a promising target for the development of novel breast cancer treatments. This pathway is activated in response to a disturbance in endoplasmic reticulum (ER) homeostasis but has diverse physiological and disease-specific functions. In breast cancer, UPR signalling promotes a malignant phenotype and can confer tumours with resistance to widely used therapies. Here, we review several roles for UPR signalling in breast cancer, highlighting UPR-mediated therapy resistance and the potential for targeting the UPR alone or in combination with existing therapies.

scholarly journals Feedback Inhibition of the Unfolded Protein Response by GADD34-Mediated Dephosphorylation of eIF2α

2001 ◽  
Vol 153 (5) ◽  
pp. 1011-1022 ◽  
Author(s):  
Isabel Novoa ◽  
Huiqing Zeng ◽  
Heather P. Harding ◽  
David Ron
Keyword(s):  
Unfolded Protein Response ◽  
Feedback Inhibition ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Α Subunit ◽  
Unfolded Protein ◽  
New Genes ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response

Phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) on serine 51 integrates general translation repression with activation of stress-inducible genes such as ATF4, CHOP, and BiP in the unfolded protein response. We sought to identify new genes active in this phospho-eIF2α–dependent signaling pathway by screening a library of recombinant retroviruses for clones that inhibit the expression of a CHOP::GFP reporter. A retrovirus encoding the COOH terminus of growth arrest and DNA damage gene (GADD)34, also known as MYD116 (Fornace, A.J., D.W. Neibert, M.C. Hollander, J.D. Luethy, M. Papathanasiou, J. Fragoli, and N.J. Holbrook. 1989. Mol. Cell. Biol. 9:4196–4203; Lord K.A., B. Hoffman-Lieberman, and D.A. Lieberman. 1990. Nucleic Acid Res. 18:2823), was isolated and found to attenuate CHOP (also known as GADD153) activation by both protein malfolding in the endoplasmic reticulum, and amino acid deprivation. Despite normal activity of the cognate stress-inducible eIF2α kinases PERK (also known as PEK) and GCN2, phospho-eIF2α levels were markedly diminished in GADD34-overexpressing cells. GADD34 formed a complex with the catalytic subunit of protein phosphatase 1 (PP1c) that specifically promoted the dephosphorylation of eIF2α in vitro. Mutations that interfered with the interaction with PP1c prevented the dephosphorylation of eIF2α and blocked attenuation of CHOP by GADD34. Expression of GADD34 is stress dependent, and was absent in PERK−/− and GCN2−/− cells. These findings implicate GADD34-mediated dephosphorylation of eIF2α in a negative feedback loop that inhibits stress-induced gene expression, and that might promote recovery from translational inhibition in the unfolded protein response.

scholarly journals An Emerging Role for the Unfolded Protein Response in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 261
Author(s):  
Claire M. Robinson ◽  
Aaron Talty ◽  
Susan E. Logue ◽  
Katarzyna Mnich ◽  
Adrienne M. Gorman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Unfolded Protein Response ◽  
Cellular Response ◽  
Tumour Microenvironment ◽  
Pancreatic Stellate Cells ◽  
Paracrine Signalling ◽  
Unfolded Protein ◽  
Pancreatic Cancer Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and one of the leading causes of cancer-associated deaths in the world. It is characterised by dismal response rates to conventional therapies. A major challenge in treatment strategies for PDAC is the presence of a dense stroma that surrounds the tumour cells, shielding them from treatment. This unique tumour microenvironment is fuelled by paracrine signalling between pancreatic cancer cells and supporting stromal cell types including the pancreatic stellate cells (PSC). While our molecular understanding of PDAC is improving, there remains a vital need to develop effective, targeted treatments. The unfolded protein response (UPR) is an elaborate signalling network that governs the cellular response to perturbed protein homeostasis in the endoplasmic reticulum (ER) lumen. There is growing evidence that the UPR is constitutively active in PDAC and may contribute to the disease progression and the acquisition of resistance to therapy. Given the importance of the tumour microenvironment and cytokine signalling in PDAC, and an emerging role for the UPR in shaping the tumour microenvironment and in the regulation of cytokines in other cancer types, this review explores the importance of the UPR in PDAC biology and its potential as a therapeutic target in this disease.

scholarly journals Heat Shock Protein 90 Modulates the Unfolded Protein Response by Stabilizing IRE1α

2002 ◽  
Vol 22 (24) ◽  
pp. 8506-8513 ◽  
Author(s):  
Monica G. Marcu ◽  
Melissa Doyle ◽  
Anne Bertolotti ◽  
David Ron ◽  
Linda Hendershot ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Specific Inhibitor ◽  
Transcriptional Response ◽  
Heat Shock Protein 90 ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
And Function ◽  
Protein Response

ABSTRACT The molecular chaperone HSP90 regulates stability and function of multiple protein kinases. The HSP90-binding drug geldanamycin interferes with this activity and promotes proteasome-dependent degradation of most HSP90 client proteins. Geldanamycin also binds to GRP94, the HSP90 paralog located in the endoplasmic reticulum (ER). Because two of three ER stress sensors are transmembrane kinases, namely IRE1α and PERK, we investigated whether HSP90 is necessary for the stability and function of these proteins. We found that HSP90 associates with the cytoplasmic domains of both kinases. Both geldanamycin and the HSP90-specific inhibitor, 514, led to the dissociation of HSP90 from the kinases and a concomitant turnover of newly synthesized and existing pools of these proteins, demonstrating that the continued association of HSP90 with the kinases was required to maintain their stability. Further, the previously reported ability of geldanamycin to stimulate ER stress-dependent transcription apparently depends on its interaction with GRP94, not HSP90, since geldanamycin but not 514 led to up-regulation of BiP. However, this effect is eventually superseded by HSP90-dependent destabilization of unfolded protein response signaling. These data establish a role for HSP90 in the cellular transcriptional response to ER stress and demonstrate that chaperone systems on both sides of the ER membrane serve to integrate this signal transduction cascade.

Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 3. Orchestrating the unfolded protein response in oncogenesis: an update

2014 ◽  
Vol 307 (10) ◽  
pp. C901-C907 ◽  
Author(s):  
Serge N. Manié ◽  
Justine Lebeau ◽  
Eric Chevet
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Dependent Manner ◽  
Cellular Mechanisms ◽  
Unfolded Protein ◽  
Stress Sensors ◽  
Plasma Membrane Receptor ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response

The endoplasmic reticulum (ER)-induced unfolded protein response (UPR) is an adaptive mechanism that is activated upon accumulation of misfolded proteins in the ER and aims at restoring ER homeostasis. In the past 10 years, the UPR has emerged as an important actor in the different phases of tumor growth. The UPR is transduced by three major ER resident stress sensors, which are protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme-1 (IRE1). The signaling pathways elicited by those stress sensors have connections with metabolic pathways and with other plasma membrane receptor signaling networks. As such, the ER has an essential position as a signal integrator in the cell and is instrumental in the different phases of tumor progression. Herein, we describe and discuss the characteristics of an integrated signaling network that might condition the UPR biological outputs in a tissue- or stress-dependent manner. We discuss these issues in the context of the pathophysiological roles of UPR signaling in cancers.

scholarly journals Flavivirus Infection Activates the XBP1 Pathway of the Unfolded Protein Response To Cope with Endoplasmic Reticulum Stress

2006 ◽  
Vol 80 (23) ◽  
pp. 11868-11880 ◽  
Author(s):  
Chia-Yi Yu ◽  
Yun-Wei Hsu ◽  
Ching-Len Liao ◽  
Yi-Ling Lin
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Cellular Response ◽  
Nonstructural Protein ◽  
Hydrophobic Membrane ◽  
Potent Inducer ◽  
Unfolded Protein ◽  
Virus Serotype ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT The unfolded protein response (UPR) is a coordinated change in gene expression triggered by perturbations in functions of the endoplasmic reticulum (ER). XBP1, a key transcription factor of the UPR, is activated by an IRE1-mediated splicing event, which results in a frameshift and encodes a protein with transcriptional activity. Here, we report that XBP1 was activated during flaviviral infection, as evidenced by XBP1 mRNA splicing and protein expression, as well as induction of the downstream genes ERdj4, EDEM1, and p58(IPK) in Japanese encephalitis virus (JEV)- and dengue virus serotype 2 (DEN-2)-infected cells. Reporter systems based on IRE1-mediated XBP1 splicing were established, and several flaviviral proteins associated with the ER, including glycoproteins and small hydrophobic membrane-anchored proteins, were found to trigger the splicing event. Notably, nonstructural protein NS2B-3 of DEN-2, but not of JEV, was a potent inducer of XBP1 splicing through an unclear mechanism(s). Reduction of XBP1 by a small interfering RNA had no effect on cells' susceptibility to the two viruses but exacerbated the flavivirus-induced cytopathic effects. Overall, flaviviruses trigger the XBP1 signaling pathway and take advantage of this cellular response to alleviate virus-induced cytotoxicity.

Dose-dependent beneficial effect of melatonin on obesity; interaction of melatonin and leptin

2019 ◽  
Vol 2 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Yaiza Potes ◽  
Beatriz De Luxán-Delgado ◽  
Adrian Rubio-González ◽  
Russel J. Reiter ◽  
Ana Maria Coto Montes
Keyword(s):  
Unfolded Protein Response ◽  
Metabolic Diseases ◽  
Tissue Specific ◽  
Unfolded Protein ◽  
Muscle Tissues ◽  
Melatonin Administration ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response ◽  
Dose Dependent

Although numerous studies have noted leptin’s role in obesity, there are still important mechanisms insights that need to be elucidated. Disturbed leptin production is associated with eating disorders, leading to alter food intake and energy expenditure. Proper regulation of protein homeostasis is critical for metabolic diseases such as obesity. Thus, the purpose of the present work was to study the unfolded protein response, which is implicated in the alleviation of endoplasmic reticulum stress-dependent dysregulation of nutritional status. We studied the effect of leptin deficiency on liver, brain and skeletal muscle tissues in obese (ob/ob) mice and the actions of a daily melatonin administration, as a possible treatment. Our findings showed that the leptin-deficient mice presented tissue-specific alterations of the three adaptive unfolded protein responses. ATF6α arm is strongly activated in all of them, indicating a deregulated lipid metabolism by the lack of leptin. Likewise, melatonin also alleviates unfolded protein response in a tissue-specific manner, acting mainly in the restoration of this disturbed ATF6α pathway. These findings support the use of melatonin as a potential therapeutic treatment against leptin-associated disorders.  

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