title: 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.affiliation: Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.8, Lleida 25198, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Macià
authors.affiliation: Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.8, Lleida 25198, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Vaquero
authors.affiliation: Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.8, Lleida 25198, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Gou-Fàbregas
authors.affiliation: Department of Endocrinology, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Lleida 25198, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Castelblanco
authors.affiliation: Department of Experimental Nephrology, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Lleida 25198, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Valdivielso
authors.affiliation: Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.8, Lleida 25198, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Anerillas
authors.affiliation: Department of Endocrinology, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Lleida 25198, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Mauricio
authors.affiliation: Department of Pathology, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Rovira Roure, 80, Lleida 25198, Spain.
authors.forename: X
authors.initials: X
authors.lastname: Matias-Guiu
authors.affiliation: Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.8, Lleida 25198, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Ribera
authors.affiliation: Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.8, Lleida 25198, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Encinas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; C486055:SPRY1 protein, human; C425468:Spry1 protein, mouse