Modulation of the unfolded protein response by GRP78 in prostate cancer.
The unfolded protein response (UPR) is an adaptive survival mechanism through which cells can weather the stress of misfolded protein accumulation induced by a wide variety of pathophysiologic and pharmacologic insults. The ER chaperone GRP78 is a central modulator of the UPR both through its protein-binding capacity and its direct regulation of the UPR signaling molecules IRE1α, PERK, and ATF6. Recent reports have revealed the presence of GRP78 on the surface of cancer cells. Biological roles for cell-surface GRP78 include competing NH(2)-domain and COOH-domain agonist receptor activities that induce opposite effects on proliferation and apoptosis. Modulation of the UPR impacts both of these processes directly and indirectly. Here, we outline methods that we use to investigate UPR modulation via direct ligation of cell-surface GRP78. Specifically, we review methods of cell culture, cell-signaling analysis with emphasis on UPR components, and ultimately, the impact that these have on cell proliferation, survival, and apoptosis.
Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.
Gustaaf
G
de Ridder
Rupa
R
Ray
Uma K
UK
Misra
Salvatore V
SV
Pizzo
D051702:Activating Transcription Factor 6 / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000502:physiology; D006360:Heat-Shock Proteins / Q000276:immunology / Q000502:physiology*; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D015398:Signal Transduction; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000502:physiology
D051702:Activating Transcription Factor 6; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C000717247:HSPA5 protein, human; C528229:ERN1 protein, human