TY - JOUR
TI - ERp29 regulates response to doxorubicin by a PERK-mediated mechanism
AU - Farmaki, E.
AU - Mkrtchian, S.
AU - Papazian, I.
AU - Papavassiliou, A. G.
AU - and Kiaris, H.
JO - Biochimica et Biophysica Acta.  Molecular Cell Research
PY - 2011
VL - 1813
TODO - 6
SP - 1165-1171
PB - ELSEVIER SCIENCE BV
SN - 0167-4889
TODO - 10.1016/j.bbamcr.2011.03.003
TODO - PERK; ERp29; ER stress; Chemotherapy; Adriamycin; UPR
TODO - ERp29 is an endoplasmic reticulum (ER) luminal protein with a putative
secretion factor/escort chaperone function. Accumulated evidence has
implicated ERp29 in the thyroglobulin secretion, polyoma virus transport
and recently in carcinogenesis. ERp29 levels were elevated in the tumors
of various origins and under the conditions of genotoxic stress, such as
ionizing radiation. Here we report the induction of ERp29 during the
treatment of cells with doxorubicin, a commonly used antineoplastic
agent. Experiments in the p53 -/- cells and p53 knockout mouse revealed
that doxorubicin effect on ERp29 is p53 dependent. The increase of ERp29
level appears to activate a negative feedback loop where the elevated
amounts of ERp29 augment cell viability as shown by a clonogenic cell
survival assay. To elucidate the mechanisms behind the doxorubicin
effects we have studied the impact of ERp29 on the interaction with the
ER stress-activated eukaryotic translation initiation factor 2-alpha
kinase 3 (PERK) that was shown to facilitate tumor cells’ resistance to
drug toxicity. Co-immunoprecipitation demonstrated physical interaction
of ERp29 with PERK and moreover, overexpression of ERp29 enhanced
endogenous levels of PERK. Our results identify ERp29 as a novel
regulator of PERK and provide evidence for the role of ER resident
factors in the regulation of chemotherapeutic efficacy. These findings
show that PERK may represent a nodal point between ER stress and
chemotherapeutic response. (C) 2011 Elsevier B.V. All rights reserved.
ER -