Role of GRP78 and its novel cytosolic isoform GRP78va in regulating the unfolded protein response in cancer

TL;DRAbstract

The endoplasmic reticulum (ER) is an essential cellular compartment for protein synthesis and maturation and also functions as a Ca2+ storage organelle. The failure of the ER to cope with the excessive protein load due to perturbation of ER functions leads to ER stress. In response to ER stress, the unfolded protein response (UPR) is activated to reduce the unfolded protein load and meanwhile increase protein folding capacity. Activation of PERK (PKR-like eIF2a kinase) signaling and induction of ER chaperone GRP78/BiP (78kDa glucose-regulated protein) represent two major survival arms of the UPR. In this thesis, the fortuitous discovery of a novel cytosolic isoform of GRP78 is reported. This GRP78 isoform, designated as GRP78va, is generated by alternative splicing and alternative translational initiation. Expression of GRP78va is enhanced by ER stress and is notably elevated in human leukemic cells and leukemia patients. Unlike the canonical form of GRP78 which is primarily localized

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