Journal ArticleDOI
Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase
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TLDR
The cloning of perk is described, a gene encoding a type I transmembrane ER-resident protein that contains a protein-kinase domain most similar to that of the known eIF2α kinases, PKR and HRI that implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.Abstract:
Protein synthesis and the folding of the newly synthesized proteins into the correct three-dimensional structure are coupled in cellular compartments of the exocytosis pathway by a process that modulates the phosphorylation level of eukaryotic initiation factor-2alpha (eIF2alpha) in response to a stress signal from the endoplasmic reticulum (ER). Activation of this process leads to reduced rates of initiation of protein translation during ER stress. Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. PERK has a lumenal domain that is similar to the ER-stress-sensing lumenal domain of the ER-resident kinase Ire1, and a cytoplasmic portion that contains a protein-kinase domain most similar to that of the known eIF2alpha kinases, PKR and HRI. ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. These properties implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.read more
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Journal ArticleDOI
PERK Regulates the Proliferation and Development of Insulin-Secreting Beta-Cell Tumors in the Endocrine Pancreas of Mice
TL;DR: PerK has two roles in the development of beta-cell insulinomas, first to support rapid cell proliferation during the initial transition to islet hyperplasia and later to promote angiogenesis during the progression to late-stage encapsulated tumors.
Journal ArticleDOI
Unfolded protein response is involved in the pathology of human congenital hypothyroid goiter and rat non-goitrous congenital hypothyroidism
Mikhail Baryshev,Ernest Sargsyan,G. Wallin,A. Lejnieks,S. Furudate,Akira Hishinuma,Souren Mkrtchian +6 more
TL;DR: Earlier observations of ER chaperone induction are extended with the identification of the additional ER (ERp29, ERp72, calreticulin, protein disulfide isomerase (PDI)), cytoplasmic and mitochondrial upregulated chaperones and folding enzymes.
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Quercetin suppresses DNA double-strand break repair and enhances the radiosensitivity of human ovarian cancer cells via p53-dependent endoplasmic reticulum stress pathway.
TL;DR: Results indicated that quercetin acted as a promising radiosensitizer through p53-dependent ER stress signals, accompanied with the activation of p53, CCAAT/enhancer-binding protein homologous protein, and γ-H2AX in human ovarian cancer xenograft model.
Journal ArticleDOI
The neuroprotective effect of salubrinal in a mouse model of traumatic brain injury.
Vardit Rubovitch,Shani Barak,Lital Rachmany,Renana Baratz Goldstein,Yael Zilberstein,Chaim G. Pick +5 more
TL;DR: The results show that targeting the translational/adaptive arm of the ISR with salubrinal may serve as a therapeutic strategy for brain damage.
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Small molecule strategies to harness the unfolded protein response: where do we go from here?
TL;DR: Currently available UPR modulating compounds are described, specifically highlighting the strategies used for their discovery and specific advantages and disadvantages in their application for probing UPR function.
References
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Journal ArticleDOI
Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.
Caroline E. Shamu,Peter Walter +1 more
TL;DR: Molecular genetic and biochemical studies described here suggest that, as in the case of growth factor receptors of higher eukaryotic cells, Ire1p oligomerizes in response to the accumulation of unfolded proteins in the ER and is phosphorylated in trans by otherIre1p molecules as a result of oligomerization.
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Protein folding in the cell.
TL;DR: Folding and assembly of polypeptides in vivo involves other proteins, many of which belong to families that have been highly conserved during evolution.
Journal ArticleDOI
The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins
TL;DR: Testing the hypothesis that the presence of malfolded proteins may be the primary signal for induction of GRPs by expressing wild-type and mutant forms of influenza virus haemagglutinin in simian cells shows that malfoldingper se, rather than abnormal glycosylation1, is the proximal inducer of this family of stress proteins.
Journal ArticleDOI
Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase
TL;DR: IRE1 encodes a transmembrane serine/threonine kinase that it is proposed transmits the unfolded protein signal across the ER or inner nuclear membrane, suggesting that the induction of ER resident proteins is coupled to the biogenesis of new ER membrane.
Journal ArticleDOI
A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells
TL;DR: HIre1p is an essential proximal sensor of the unfolded protein response pathway in mammalian cells and is demonstrated to be highly conserved to the yeast counterpart having a Ser/Thr protein kinase domain and a domain homologous to RNase L.