Abstract
Ataxia telangiectasia mutated (ATM) kinase plays a crucial role in the cellular response to DNA damage and in radiation resistance. Although much effort has focused on the relationship between ATM and other nuclear signal transducers, little is known about interactions between ATM and mitogenic signaling pathways. In this study, we show a novel relationship between ATM kinase and extracellular signal-regulated kinase 1/2 (ERK1/2), a key mitogenic stimulator. Activation of ATM by radiation down-regulates phospho-ERK1/2 and its downstream signaling via increased expression of mitogen-activated protein kinase phosphatase MKP-1 in both cell culture and tumor models. This dephosphorylation of ERK1/2 is independent of epidermal growth factor receptor (EGFR) activity and is associated with radioresistance. These findings show a new function for ATM in the control of mitogenic pathways affecting cell signaling and emphasize the key role of ATM in coordinating the cellular response to DNA damage.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigens, Differentiation / genetics*
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Ataxia Telangiectasia Mutated Proteins
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Carcinoma, Squamous Cell / genetics*
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Carcinoma, Squamous Cell / pathology
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Carcinoma, Squamous Cell / radiotherapy
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Cell Cycle Proteins / genetics*
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Cell Cycle Proteins / metabolism*
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Cell Cycle Proteins / radiation effects*
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Cell Line, Tumor
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Cell Survival
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DNA Damage
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DNA Replication
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DNA-Binding Proteins / genetics*
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Dual Specificity Phosphatase 1
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Enzyme Activation
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Gene Expression Regulation, Neoplastic*
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Humans
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Immediate-Early Proteins / metabolism*
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Immediate-Early Proteins / radiation effects*
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Membrane Glycoproteins / genetics*
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Mice
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Mice, Nude
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Neural Cell Adhesion Molecules / genetics*
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Phosphoprotein Phosphatases / metabolism*
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Phosphoprotein Phosphatases / radiation effects*
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Polymerase Chain Reaction
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Protein Phosphatase 1
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Protein Serine-Threonine Kinases / genetics*
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Protein Tyrosine Phosphatases / metabolism*
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Protein Tyrosine Phosphatases / radiation effects*
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RNA, Neoplasm / genetics
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RNA, Neoplasm / isolation & purification
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Receptors, Immunologic / genetics*
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Transplantation, Heterologous
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Tumor Suppressor Proteins / genetics*
Substances
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Antigens, Differentiation
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Cell Cycle Proteins
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DNA-Binding Proteins
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Immediate-Early Proteins
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Membrane Glycoproteins
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Neural Cell Adhesion Molecules
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RNA, Neoplasm
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Receptors, Immunologic
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SIRPA protein, human
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SIRPB2 protein, human
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Tumor Suppressor Proteins
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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Phosphoprotein Phosphatases
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Protein Phosphatase 1
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DUSP1 protein, human
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Dual Specificity Phosphatase 1
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Dusp1 protein, mouse
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Protein Tyrosine Phosphatases