Abstract
Endoplasmic reticulum stress (ER-stress) is associated with ataxia telangiectasia mutated (ATM) gene. We present here conclusive data showing that ATM blocks ER-stress induced by tunicamycin or ionizing radiation (IR). X-box protein-1 (XBP-1) splicing, GRP78 expression and caspase-12 activation were increased by tunicamycin or IR in Atm-deficient AT5BIVA fibroblasts. Activation of caspase-12 and caspase-3 by tunicamycin was significantly reduced in cells transfected with wild-type Atm (AT5BIVA/wtATM). Atm knockdown by siRNA, however, noticeably elevated ER-stress and chemosensitivity to tunicamycin. In summary, we present substantial data demonstrating that ATM blocks the ER stress signaling associated with cancer cell proliferation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Ataxia Telangiectasia Mutated Proteins
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Caspase 12 / metabolism
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Caspase 3 / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Endoplasmic Reticulum / drug effects*
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Endoplasmic Reticulum / metabolism*
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Endoplasmic Reticulum / radiation effects
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Enzyme Activation / drug effects
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Humans
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Protein-Serine-Threonine Kinases / deficiency
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Protein-Serine-Threonine Kinases / genetics
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Protein-Serine-Threonine Kinases / metabolism*
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RNA, Small Interfering / genetics
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Stress, Physiological / drug effects*
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Stress, Physiological / radiation effects
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Tunicamycin / pharmacology*
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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RNA, Small Interfering
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Tumor Suppressor Proteins
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Tunicamycin
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein-Serine-Threonine Kinases
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Caspase 12
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Caspase 3