Nijmegen breakage syndrome fibroblasts expressing the C-terminal truncated NBN(p70) protein undergo p38/MK2-dependent premature senescence.

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.

• Authors: Terence Davis, Hannah S E Tivey, Amy J C Brook, David Kipling
• Journal: Biogerontology (Biogerontology) Vol. 16 Issue 1 Pg. 43-51 (Feb 2015) ISSN: 1573-6768 [Electronic] Netherlands
• PMID: 25214013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Enzyme Inhibitors
• Imidazoles
• Intracellular Signaling Peptides and Proteins
• NBN protein, human
• Nuclear Proteins
• Pyridines
• MAP-kinase-activated kinase 2
• Protein Serine-Threonine Kinases
• p38 Mitogen-Activated Protein Kinases
• SB 203580

Topics

• Cell Cycle Proteins (metabolism)
• Cell Proliferation (physiology)
• Cells, Cultured
• Cellular Senescence (physiology)
• Enzyme Inhibitors (pharmacology)
• Fibroblasts (metabolism, pathology)
• Humans
• Imidazoles (pharmacology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Nijmegen Breakage Syndrome (metabolism, pathology)
• Nuclear Proteins (metabolism)
• Phenotype
• Protein Serine-Threonine Kinases (metabolism)
• Pyridines (pharmacology)
• Signal Transduction (drug effects, physiology)
• Telomere (physiology)
• p38 Mitogen-Activated Protein Kinases (metabolism)