Small Molecule Inhibition of p38 MAP Kinase Extends the Replicative Life Span of Human ATR-Seckel Syndrome Fibroblasts
| Autor: | James R. Barnacle, Mathew James Rogers, David Glyn Kipling, Terence Davis, Michal Jaroslaw Rokicki, Hannah S. E. Tivey, Mark C. Bagley |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Senescence
Premature aging p53 Aging Telomerase MAP Kinase Signaling System Caveolin 1 Cell Cycle Proteins Dwarfism Ataxia Telangiectasia Mutated Proteins Biology Protein Serine-Threonine Kinases p38 Mitogen-Activated Protein Kinases Progeroid syndromes RC0254 medicine Humans RNA Small Interfering Protein kinase A Protein Kinase Inhibitors Cells Cultured Cellular Senescence Werner syndrome Cell Proliferation Chromosome instability Replication stress Facies Fibroblasts medicine.disease Genes p53 Actins Cell biology Seckel syndrome Telomeres ATR Caveolin-1 Mutation Cancer research Microcephaly Original Article Fragile sites Geriatrics and Gerontology RB Cell aging |
| Zdroj: | The Journals of Gerontology Series A: Biological Sciences and Medical Sciences |
| ISSN: | 1758-535X 1079-5006 |
| Popis: | Ataxia-telangiectasia and rad3 (ATR)-related Seckel syndrome is associated with growth retardation and premature aging features. ATR-Seckel fibroblasts have a reduced replicative capacity in vitro and an aged morphology that is associated with activation of stress-associated p38 mitogen-activated protein kinase and phosphorylated HSP27. These phenotypes are prevented using p38 inhibitors, with replicative capacity restored to the normal range. However, this stressed phenotype is retained in telomerase-immortalized ATR-Seckel fibroblasts, indicating that it is independent of telomere erosion. As with normal fibroblasts, senescence in ATR-Seckel is bypassed by p53 abrogation. Young ATR-Seckel fibroblasts show elevated levels of p21(WAF1), p16(INK4A), phosphorylated actin-binding protein cofilin, and phosphorylated caveolin-1, with small molecule drug inhibition of p38 reducing p16(INK4A) and caveolin-1 phosphorylation. In conclusion, ATR-Seckel fibroblasts undergo accelerated aging via stress-induced premature senescence and p38 activation that may underlie certain clinical features of Seckel syndrome, and our data suggest a novel target for pharmacological intervention in this human syndrome. |
| Databáze: | OpenAIRE |
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