Sprouty1 is a broad mediator of cellular senescence
Carlos Anerillas1,2,3, Aida Perramon-Güell4, Gisela Altés4
1Developmental and Oncogenic Signaling Group, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Rovira Roure, 80, Lleida, Spain. canerillas@cbm.csic.com.
Abstract:
Genes of the Sprouty family (Spry1-4) restrain signaling by certain receptor tyrosine kinases. Consequently, these genes participate in several developmental processes and function as tumor suppressors in adult life. Despite these important roles, the biology of this family of genes still remains obscure. Here we show that Sprouty proteins are general mediators of cellular senescence. Induction of cellular senescence by several triggers in vitro correlates with upregulation of Sprouty protein levels. More importantly, overexpression of Sprouty genes is sufficient to cause premature cellular senescence, via a conserved N-terminal tyrosine (Tyrosine 53 of Sprouty1). Accordingly, fibroblasts from knockin animals lacking that tyrosine escape replicative senescence. In vivo, heterozygous knockin mice display delayed induction of cellular senescence during cutaneous wound healing and upon chemotherapy-induced cellular senescence. Unlike other functions of this family of genes, induction of cellular senescence appears to be independent of activation of the ERK1/2 pathway. Instead, we show that Sprouty proteins induce cellular senescence upstream of the p38 pathway in these in vitro and in vivo paradigms.
Insights
Sprouty proteins mediate cellular senescence, a key aging process. Upregulation of Sprouty genes triggers premature senescence, impacting wound healing and chemotherapy responses in mice.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Sprouty genes (Spry1-4) regulate receptor tyrosine kinase signaling.
- These genes are crucial for development and act as tumor suppressors.
- The precise biological functions of Sprouty proteins remain incompletely understood.
Purpose of the Study:
- To investigate the role of Sprouty proteins in cellular senescence.
- To elucidate the molecular mechanisms by which Sprouty proteins influence senescence.
- To examine the in vivo relevance of Sprouty-mediated senescence.
Main Methods:
- Induction of cellular senescence using various triggers in vitro.
- Overexpression of Sprouty genes and analysis of senescence markers.
- Generation and analysis of knockin mice with mutations in a key Sprouty tyrosine residue.
- Assessment of senescence during wound healing and chemotherapy in vivo.
Main Results:
- Cellular senescence induction correlates with increased Sprouty protein levels.
- Sprouty gene overexpression causes premature senescence, dependent on a specific N-terminal tyrosine.
- Knockin fibroblasts lacking this tyrosine resist replicative senescence.
- In vivo studies show delayed senescence in heterozygous knockin mice during wound healing and after chemotherapy.
- Sprouty-induced senescence is independent of ERK1/2 but acts upstream of the p38 pathway.
Conclusions:
- Sprouty proteins are identified as general mediators of cellular senescence.
- A specific tyrosine residue in Sprouty proteins is critical for inducing senescence.
- Sprouty-mediated senescence operates independently of the ERK1/2 pathway, involving the p38 pathway.
- These findings reveal a novel role for Sprouty proteins in aging and stress responses.
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