couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA.
The present results demonstrated that treating HUVECs with NAC down-regulated the phosphorylation of IRE1[alpha], and the IRE1
a inhibitor (STF-083010) reduced apoptosis of HUVECs as detected by TEM and flow cytometry.
The findings have revealed shown for the first time that IRE1
, a cellular stress sensor that normally acts to alleviate shortterm stresses within cells, such as lack of nutrients or oxygen, is a central driver of treatment-related relapse.
Its lead program is a first-in-class, small molecule, IRE1
The stress relief mechanism UPR can be initiated by ER stress sensor IRE1
upon the accumulation of misfolded or unfolded proteins.
Three ER-resident proteins have been identified as sensors of ER stress: IRE1
(inositol-requiring protein 1), PERK (PKR- (double-stranded RNA-dependent protein kinase) like ER kinase), and ATF6 (activating transcription factor) .
Bertolotti et al., "Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1
," Science, vol.
Kamphuis et al., "A J-protein co-chaperone recruits BiP to monomerize IRE1
and repress the unfolded protein response," Cell, vol.
There are two IRE1
genes (IRE1[alpha] and IRE1[beta]), but only IRE1[alpha] is expressed ubiquitously.
The UPR, known to be a crucial defensive mechanism in ER stress, is mediated by three transmembrane proteins (IRE1
, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor 6).
The UPR depends on three resident sensors: inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1
), protein kinase R- (PKR-) like endoplasmic reticulum kinase (PERK), and activating transcription factor-6 (ATF6) [15, 16].
This UPR pathway is mainly initiated by ER stress sensors: PERK, ATF6 and IRE1
, and the PERK-eIF2[alpha] and IRE1-TNF receptor-associated factor 2 (TRAF2)-Jun N-terminal kinase (JNK) pathways are the leading regulators for autophagy induction.