FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence
| Autor: | Katarina Chlebova, William R. Wilcox, Patricia Lin, Anie Aklian, Vitezslav Bryja, Alois Kozubík, Pavel Krejci, Jiri Smutny, Jirina Prochazkova |
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| Rok vydání: | 2010 |
| Předmět: |
MAPK/ERK pathway
Senescence musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities Histology Physiology Endocrinology Diabetes and Metabolism Apoptosis Biology Chondrocyte Receptor tyrosine kinase Article 03 medical and health sciences 0302 clinical medicine Chondrocytes Downregulation and upregulation medicine Animals Receptor Fibroblast Growth Factor Type 3 Extracellular Signal-Regulated MAP Kinases Cell Shape Molecular Biology Cellular Senescence 030304 developmental biology Cell Proliferation 0303 health sciences Oncogene Cartilage Oncogenes Cell Biology Cell biology Extracellular Matrix Rats medicine.anatomical_structure Phenotype 030220 oncology & carcinogenesis Mitogen-activated protein kinase Caveolin 1 Cancer research biology.protein Signal transduction Cell aging Lamin Signal Transduction Developmental Biology |
| Zdroj: | Developmental Biology. 344(1) |
| ISSN: | 0012-1606 |
| DOI: | 10.1016/j.ydbio.2010.05.341 |
| Popis: | Oncogenic activation of the RAS-ERK MAP kinase signaling pathway can lead to uncontrolled proliferation but can also result in apoptosis or premature cellular senescence, both regarded as natural protective barriers to cell immortalization and transformation. In FGFR3-related skeletal dyplasias, oncogenic mutations in the FGFR3 receptor tyrosine kinase cause profound inhibition of cartilage growth resulting in severe dwarfism, although many of the precise mechanisms of FGFR3 action remain unclear. Mutated FGFR3 induces constitutive activation of the ERK pathway in chondrocytes and, remarkably, can also cause both increased proliferation and apoptosis in growing cartilage, depending on the gestational age. Here, we demonstrate that FGFR3 signaling is also capable of inducing premature senescence in chondrocytes, manifested as reversible, ERK-dependent growth arrest accompanied by alteration of cellular shape, loss of the extracellular matrix, upregulation of senescence markers (alpha-GLUCOSIDASE, FIBRONECTIN, CAVEOLIN 1, LAMIN A, SM22alpha and TIMP 1), and induction of senescence-associated beta-GALACTOSIDASE activity. Our data support a model whereby FGFR3 signaling inhibits cartilage growth via exploiting cellular responses originally designed to eliminate cells harboring activated oncogenes. |
| Databáze: | OpenAIRE |
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