Abstract
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.
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Abbreviations
- ERK:
-
Extracellular-regulated kinases
- MAPK:
-
Mitogen-activated protein kinases
- NFκB:
-
Nuclear Factor κB
- TSH:
-
Thyroid-stimulating hormone
- Pten:
-
Phosphatase and tensin homolog
- STAT3:
-
signal transducer and activator of transcription 3
- IL-6:
-
Interleukin-6
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Acknowledgements
We thank Lidia Parra, Cristina Girón, Sònia Gatius and Maria Santacana for technical support. This work was supported by grants from Ministerio de Economía y Competitividad (BFU2007-67619 and BFU2010-17628) and Fundació La Marató de TV3 (101810), and funding from Suport als Grups de Recerca (2009 SGR 740) from Generalitat de Catalunya to ME, AM is supported by a predoctoral fellowship from Universitat de Lleida and was supported by a fellowship from a Fundació Alícia Cuello de Merigó. MV is supported by a predoctoral fellowship from AGAUR (Generalitat de Catalunya). MG-F is supported by a grant from Fundació La Marató de TV3. CA was supported in part by a Beca de Colaboración (MEC).
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Macià, A., Vaquero, M., Gou-Fàbregas, M. et al. Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis. Cell Death Differ 21, 333–343 (2014). https://doi.org/10.1038/cdd.2013.161
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DOI: https://doi.org/10.1038/cdd.2013.161
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