Developmental and Oncogenic Signaling Group, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Rovira Roure, 80, Lleida, Spain.
Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, 251 Bayview Blvd., Baltimore, MD, USA.
Cell Death Dis. 2024 Apr 26;15(4):296. doi: 10.1038/s41419-024-06689-4.
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.
芽殖蛋白家族（Spry1-4）的基因抑制某些受体酪氨酸激酶的信号转导。因此，这些基因参与了几个发育过程，并在成年期作为肿瘤抑制因子发挥作用。尽管这些基因具有重要的作用，但它们的生物学功能仍然不明确。在这里，我们表明芽殖蛋白是细胞衰老的普遍介质。体外几种诱导因子诱导的细胞衰老与芽殖蛋白水平的上调相关。更重要的是，通过保守的 N 端酪氨酸（芽殖蛋白 1 的酪氨酸 53），过表达芽殖蛋白基因足以导致过早的细胞衰老。相应地，缺乏该酪氨酸的敲入动物的成纤维细胞可以逃避复制性衰老。在体内，杂合敲入小鼠在皮肤伤口愈合和化疗诱导的细胞衰老期间，细胞衰老的诱导延迟。与该基因家族的其他功能不同，细胞衰老的诱导似乎不依赖于 ERK1/2 途径的激活。相反，我们在这些体外和体内模型中表明，芽殖蛋白在 p38 途径上游诱导细胞衰老。
