Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis.

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.

• Authors: A Macià, M Vaquero, M Gou-Fàbregas, E Castelblanco, J M Valdivielso, C Anerillas, D Mauricio, X Matias-Guiu, J Ribera, M Encinas
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 21 Issue 2 Pg. 333-43 (Feb 2014) ISSN: 1476-5403 [Electronic] England
• PMID: 24270409 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Membrane Proteins
• NF-kappa B
• Phosphoproteins
• SPRY1 protein, human
• Spry1 protein, mouse

Topics

• Adaptor Proteins, Signal Transducing (deficiency, genetics, metabolism)
• Animals
• Cell Proliferation
• Cell Transformation, Neoplastic
• Cellular Senescence
• Humans
• Membrane Proteins (deficiency, genetics, metabolism)
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• Phenotype
• Phosphoproteins (deficiency, genetics, metabolism)
• Thyroid Gland (metabolism)
• Thyroid Neoplasms (genetics, metabolism, pathology)