期刊
CELL DEATH AND DIFFERENTIATION
卷 21, 期 2, 页码 333-343出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2013.161
关键词
cellular senescence; tumor suppressors; sprouty; Pten; SASP; IL-6
资金
- Ministerio de Economia y Competitividad [BFU2007-67619, BFU2010-17628]
- Fundacio La Marato de TV3 [101810]
- Grups de Recerca from Generalitat de Catalunya [2009 SGR 740]
- Universitat de Lleida
- Fundacio Alicia Cuello de Merigo
- AGAUR (Generalitat de Catalunya)
- Fundacio La Marato de TV3
- Beca de Colaboracion (MEC)
- European Foundation for the Study of Diabetes [BI 2014_6_clinical] Funding Source: researchfish
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 NF kappa B pathway. Consistently, thyroids from Spry1 knockout mice are bigger and exhibit decreased markers of senescence including Ki67 labeling and senescence-associated beta-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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据