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Up‐regulation of GRP78 and antiapoptotic signaling in murine peritoneal macrophages exposed to insulin
Author(s) -
Misra Uma Kant,
Pizzo Salvatore Vincent
Publication year - 2005
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1104685
Subject(s) - unfolded protein response , endoplasmic reticulum , tunicamycin , biology , glucose regulated protein , microbiology and biotechnology , eif 2 kinase , insulin , downregulation and upregulation , apoptosis , protein kinase a , kinase , signal transduction , insulin receptor , phosphorylation , cancer research , medicine , endocrinology , insulin resistance , cyclin dependent kinase 2 , biochemistry , gene
The unfolded protein response pathway (UPR) compensates for excessive protein accumulation in the endoplasmic reticulum (ER). As insulin induces global protein synthesis, it may cause accumulation of unfolded proteins in the ER, thus triggering UPR. We assessed UPR activation in insulin‐treated murine peritoneal macrophages using a number of markers including 78 kDa glucose response protein (GRP78), X‐box‐binding protein (XBP)‐1, pancreatic ER kinase (PERK), eukaryotic initiation factor 2 (eIF2)α, and growth arrest and DNA damage (GADD)34. Exposure of cells to insulin activated UPR, as evidenced by an increased expression of GRP78, XBP‐1, phosphorylated PERK (p‐PERK), and p‐eIF2α. The insulin‐induced, elevated expression of GRP78 was comparable with that observed with tunicamycin, a classical inducer of ER stress. Concomitantly, insulin also up‐regulated prosurvival mechanisms by elevating GADD34 and elements of the antiapoptotic pathway including Bcl‐2, X‐linked inhibitor of apoptosis, and phosphorylated forkhead transcription factor. In conclusion, we show here that insulin treatment does cause ER stress in macrophages, but insulin‐dependent mechanisms overcome this ER stress by up‐regulating UPR and the antiapoptotic pathway to promote cell survival.