TY - JOUR
T1 - Endoplasmic recticulum stress and unfolded protein response in Atm-deficient thymocytes and thymic lymphoma cells are attributable to oxidative stress
AU - Yan, Mingshan
AU - Shen, Jianjun
AU - Person, Maria D.
AU - Kuang, Xianghong
AU - Lynn, William S.
AU - Atlas, Daphne
AU - Wong, Paul K.Y.
PY - 2008/2
Y1 - 2008/2
N2 - Both oxidative stress and endoplasmic reticulum (ER) stress have been implicated in carcinogenesis. It is well documented that cells deficient in the ataxia-telangiectasia mutated (ATM) gene undergo oxidative stress, which is critically involved in thymic lymphomagenesis in Atm-/- mice. Here we demonstrate that undifferentiated Atm-/-thymocytes show signs of ER stress and of the unfolded protein response (UPR). Using two-dimensional (2-D) gel electrophoresis and mass spectrometry (MS) analysis, we identified 22 differentially expressed proteins, including the ER stress marker glucose-regulated protein 78 (GRP78), in Atm-/- thymocytes and in Atm-/- thymic lymphoma cells relative to Atm+/+ thymocytes. The phosphorylated α subunit of eukaryotic translation initiation factor 2 (p-eIF2α), a UPR marker, was also increased in Atm-/- thymocytes. Cells of the ATL-1 line, which were derived from an Atm-/- mouse thymic lymphoma, were more sensitive to the ER stress inducer tunicamycin than were Atm+/+ thymic leukemia ASL-1 cells. Notably, treatment with hydrogen peroxide duplicated the effects of ATM deficiency in cultured thymocytes, and treatment with the novel cell-permeable thiol antioxidant N-acetylcysteine amide (AD4) reduced elevated p-eIF2α levels in thymocytes of Atm-/- mice. Thus, we propose that ER stress and the UPR are secondary to oxidative stress in Atm-/- thymocytes.
AB - Both oxidative stress and endoplasmic reticulum (ER) stress have been implicated in carcinogenesis. It is well documented that cells deficient in the ataxia-telangiectasia mutated (ATM) gene undergo oxidative stress, which is critically involved in thymic lymphomagenesis in Atm-/- mice. Here we demonstrate that undifferentiated Atm-/-thymocytes show signs of ER stress and of the unfolded protein response (UPR). Using two-dimensional (2-D) gel electrophoresis and mass spectrometry (MS) analysis, we identified 22 differentially expressed proteins, including the ER stress marker glucose-regulated protein 78 (GRP78), in Atm-/- thymocytes and in Atm-/- thymic lymphoma cells relative to Atm+/+ thymocytes. The phosphorylated α subunit of eukaryotic translation initiation factor 2 (p-eIF2α), a UPR marker, was also increased in Atm-/- thymocytes. Cells of the ATL-1 line, which were derived from an Atm-/- mouse thymic lymphoma, were more sensitive to the ER stress inducer tunicamycin than were Atm+/+ thymic leukemia ASL-1 cells. Notably, treatment with hydrogen peroxide duplicated the effects of ATM deficiency in cultured thymocytes, and treatment with the novel cell-permeable thiol antioxidant N-acetylcysteine amide (AD4) reduced elevated p-eIF2α levels in thymocytes of Atm-/- mice. Thus, we propose that ER stress and the UPR are secondary to oxidative stress in Atm-/- thymocytes.
UR - http://www.scopus.com/inward/record.url?scp=39049134403&partnerID=8YFLogxK
U2 - 10.1593/neo.07935
DO - 10.1593/neo.07935
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C2 - 18283338
AN - SCOPUS:39049134403
SN - 1522-8002
VL - 10
SP - 160
EP - 167
JO - Neoplasia
JF - Neoplasia
IS - 2
ER -