Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis
| Autor: | J M Valdivielso, D. Mauricio, Xavier Matias-Guiu, Anna Macià, Mario Encinas, Marta Vaquero, Carlos Anerillas, E. Castelblanco, M Gou-Fabregas, Joan Muela Ribera |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
MAPK/ERK pathway
Senescence Mice 129 Strain Thyroid Gland Receptor tyrosine kinase Mice PTEN Tensin Animals Humans Thyroid Neoplasms Molecular Biology Cellular Senescence Adaptor Proteins Signal Transducing Cell Proliferation Mice Knockout Original Paper biology Kinase NF-kappa B Membrane Proteins Cell Biology NFKB1 Phosphoproteins Cell biology Mice Inbred C57BL Cell Transformation Neoplastic Phenotype biology.protein Cell aging |
| Popis: | Genes of the Sprouty family (Spry1–4) are feedback inhibitors of receptor tyrosine kinase (RTK) signaling. As such, they restrain proliferation of many cell types and have been proposed as tumor-suppressor genes. Although their most widely accepted target is the Extracellular-regulated kinases (ERK) pathway, the mechanisms by which Spry proteins inhibit RTK signaling are poorly understood. In the present work, we describe a novel mechanism by which Spry1 restricts proliferation, independently of the ERK pathway. In vivo analysis of thyroid glands from Spry1 knockout mice reveals that Spry1 induces a senescence-associated secretory phenotype via activation of the NFκB pathway. Consistently, thyroids from Spry1 knockout mice are bigger and exhibit decreased markers of senescence including Ki67 labeling and senescence-associated β-galactosidase. Although such ‘escape' from senescence is not sufficient to promote thyroid tumorigenesis in adult mice up to 5 months, the onset of Phosphatase and tensin homolog (Pten)-induced tumor formation is accelerated when Spry1 is concomitantly eliminated. Accordingly, we observe a reduction of SPRY1 levels in human thyroid malignancies when compared with non-tumoral tissue. We propose that Spry1 acts as a sensor of mitogenic activity that not only attenuates RTK signaling but also induces a cellular senescence response to avoid uncontrolled proliferation. |
| Databáze: | OpenAIRE |
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