Abstract
Fibroblasts from the progeroid Nijmegen breakage syndrome that express a truncated version of the nibrin protein (NBN(p70)) undergo premature senescence and have an enlarged morphology with high levels of senescence-associated β-galactosidase, although they do not have F-actin stress fibres. Growth of these fibroblasts in the continuous presence of p38 inhibitors resulted in a large increase in replicative capacity and changed the cellular morphology so that the cells resembled young normal fibroblasts. A similar effect was seen using an inhibitor of the p38 downstream effector kinase MK2. These data suggest that NBN(p70) expressing cells undergo a degree of stress-induced replicative senescence via p38/MK2 activation, potentially due to increased telomere dysfunction, that may play a role in the progeroid features seen in this syndrome.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle Proteins / metabolism*
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Cell Proliferation / physiology
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Cells, Cultured
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Cellular Senescence / physiology*
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Enzyme Inhibitors / pharmacology
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Fibroblasts / metabolism
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Fibroblasts / pathology*
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Humans
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Imidazoles / pharmacology
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Intracellular Signaling Peptides and Proteins / metabolism*
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Nijmegen Breakage Syndrome / metabolism
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Nijmegen Breakage Syndrome / pathology*
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Nuclear Proteins / metabolism*
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Phenotype
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Protein Serine-Threonine Kinases / metabolism*
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Pyridines / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Telomere / physiology
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Cell Cycle Proteins
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Enzyme Inhibitors
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Imidazoles
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Intracellular Signaling Peptides and Proteins
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NBN protein, human
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Nuclear Proteins
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Pyridines
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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p38 Mitogen-Activated Protein Kinases
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SB 203580