Yosef Reut, Pilpel Noam, Papismadov Nurit, Gal Hilah, Ovadya Yossi, Vadai Ezra, Miller Stav, Porat Ziv, Ben-Dor Shifra, Krizhanovsky Valery
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
Life Sciences Core Facilities, The Weizmann Institute of Science, Rehovot, Israel.
EMBO J. 2017 Aug 1;36(15):2280-2295. doi: 10.15252/embj.201695553. Epub 2017 Jun 12.
Cellular senescence is a permanent state of cell cycle arrest that protects the organism from tumorigenesis and regulates tissue integrity upon damage and during tissue remodeling. However, accumulation of senescent cells in tissues during aging contributes to age-related pathologies. A deeper understanding of the mechanisms regulating the viability of senescent cells is therefore required. Here, we show that the CDK inhibitor p21 (CDKN1A) maintains the viability of DNA damage-induced senescent cells. Upon p21 knockdown, senescent cells acquired multiple DNA lesions that activated ataxia telangiectasia mutated (ATM) and nuclear factor (NF)-κB kinase, leading to decreased cell survival. NF-κB activation induced TNF-α secretion and JNK activation to mediate death of senescent cells in a caspase- and JNK-dependent manner. Notably, p21 knockout in mice eliminated liver senescent stellate cells and alleviated liver fibrosis and collagen production. These findings define a novel pathway that regulates senescent cell viability and fibrosis.
细胞衰老 是一种细胞周期停滞的永久状态，可保护机体免受肿瘤发生，并在组织损伤和重塑过程中调节组织完整性。然而，衰老过程中组织内衰老细胞的积累会导致与年龄相关的病理变化。因此，需要更深入地了解调节衰老细胞活力的机制。在此，我们表明细胞周期蛋白依赖性激酶（CDK）抑制剂p21（CDKN1A）维持DNA损伤诱导的衰老细胞的活力。p21基因敲低后，衰老细胞出现多个DNA损伤，激活了共济失调毛细血管扩张突变蛋白（ATM）和核因子（NF）-κB激酶，导致细胞存活率下降。NF-κB激活诱导肿瘤坏死因子-α（TNF-α）分泌和c-Jun氨基末端激酶（JNK）激活，以半胱天冬酶和JNK依赖的方式介导衰老细胞死亡。值得注意的是，小鼠中p21基因敲除消除了肝脏衰老的星状细胞，减轻了肝纤维化和胶原蛋白生成。这些发现定义了一条调节衰老细胞活力和纤维化的新途径。
