ERN1

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ERN1

A gene on chromosome 17q24.2 that encodes the ubiquitously expressed endoplasmic reticulum (ER)-to-nucleus signalling 1 protein, which has intrinsic kinase and endoribonuclease activities and plays a key role in altering gene expression in response to endoplasmic reticulum-based stress signals. ERN1 senses unfolded proteins in the ER lumen, leading to enzyme auto-activation; the active endoribonuclease domain splices XBP1 mRNA, generating a new C-terminus and converting it into a potent unfolded-protein response transcriptional activator, triggering growth arrest and apoptosis.
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IRE1, which resides in the endoplasmic reticulum of cells, has been implicated in stress-related cell death through its ability to activate an enzyme called JNK.
A component of the UPR known as the IRE1 pathway has generally been thought to handle the protective aspects of this response, promoting cell survival by providing cells with the biological resources they need to cope with stress, while a complementary pathway, called PERK, has been associated with cell death.
the molecular sensor that triggers the IRE1 pathway they blocked cell death and preserved function in experimental models of two human diseases.
The results are the culmination of a gigantic project, first to establish that the IRE1 pathway could drive degenerative disease, and then to design and test compounds to head off the damage, said UCSF s Feroz Papa, MD, PhD, associate professor of medicine and co-senior author, and a member of the California Institute for Quantitative Biosciences.
Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1.
Treatment of BFP also increased a number of signature endoplasmic reticulum (ER) stress markers glucose-regulated protein (GRP)-78, GRP-94, IRE1, phosphorylation of eukaryotic initiation factor-2[alpha] (eIF-2[alpha]) and up-regulation of CAATienhancer-binding protein homologous protein (CHOP).
Primary antibodies specific for calpain 1, IRE1, GRP78, GRP94, PARP, pro-caspase 3, pro-caspase 9, pro-caspase 7 and 13-actin were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA).
5A, BFP-induced IRE1 increase, and procaspase-3 and procaspase-9 degradation were reversed by treatment with two different antioxidants apocynin (10 [micro]M) and N-acetylcysteine (NAC, 10 mM).
The pre-clinical study, conducted by researchers at Dana-Farber Cancer Institute in collaboration with MannKind Corporation (Nasdaq: MNKD), confirm that blocking the XBP1 arm of the unfolded protein response with MannKind's novel, first-in-class IRE1 RNase domain inhibitor, MKC-3946, alone or in combination with bortezomib or 17AAG, inhibited growth in multiple myeloma cells, while leaving normal cells intact.
Our findings show that targeting the XBP1 pathway with a selective IRE1 inhibitor, in this case the small molecule inhibitor MKC-3946, is a promising therapeutic strategy, providing the preclinical basis for future trials evaluating the clinical efficacy of this approach to improve patient outcomes in multiple myeloma.
PTP1B has been shown very recently to potentiate IRE1 signaling during ER stress (Gu et al.
It is thus thought to be an important marker reflecting both IRE1 and ATF6 signaling in response to ER stress.