Zhang Yongjin, Shao Chihao, Li Haili, Wu Kun, Gong Lixin, Zheng Quan, Dan Juhua, Jia Shuting, Tang Xiaodan, Wu Xiaoming, Luo Ying
Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Kunming, China.
Guizhou Provincial Key Laboratory of Pathogenesis & Drug Development on Common Chronic Diseases, School of Basic Medicine, Guizhou Medical University, Guiyang, China.
Front Genet. 2021 Feb 5;12:597566. doi: 10.3389/fgene.2021.597566. eCollection 2021.
Human Werner syndrome (WS) is an autosomal recessive progeria disease. A mouse model of WS manifests the disease through telomere dysfunction-induced aging phenotypes, which might result from cell cycle control and cellular senescence. Both p21 (p21, encoded by the gene) and p16 (p16, encoded by the gene) are cell cycle inhibitors and are involved in regulating two key pathways of cellular senescence. To test the effect of p21 and p16 deficiencies in WS, we crossed WS mice (DKO) with or mice to construct triple knockout (p21-TKO or p16-TKO) mice. By studying the survival curve, bone density, regenerative tissue (testis), and stem cell capacity (intestine), we surprisingly found that p21-TKO mice displayed accelerated premature aging compared with DKO mice, while p16-TKO mice showed attenuation of the aging phenotypes. The incidence of apoptosis and cellular senescence were upregulated in p21-TKO mice tissue and downregulated in p16-TKO mice. Surprisingly, cellular proliferation in p21-TKO mice tissue was also upregulated, and the p21-TKO mice did not show telomere shortening compared with age-matched DKO mice, although p16-TKO mice displayed obvious enhancement of telomere lengthening. Consistent with these phenotypes, the SIRT1-PGC1 pathway was upregulated in p16-TKO but downregulated in p21-TKO compared with DKO mouse embryo fibroblasts (MEFs). However, the DNA damage response pathway was highly activated in p21-TKO, but rescued in p16-TKO, compared with DKO MEFs. These data suggest that p21 protected the stem cell reservoir by regulating cellular proliferation and turnover at a proper rate and that p21 loss in WS activated fairly severe DNA damage responses (DDR), which might cause an abnormal increase in tissue homeostasis. On the other hand, p16 promoted cellular senescence by inhibiting cellular proliferation, and p16 deficiency released this barrier signal without causing severe DDR.
人类沃纳综合征（WS）是一种常染色体隐性早衰疾病。WS小鼠模型通过端粒功能障碍诱导的衰老表型表现出该疾病，这可能是由细胞周期控制和细胞衰老导致的。p21（由该基因编码的p21）和p16（由该基因编码的p16）都是细胞周期抑制剂，参与调节细胞衰老的两个关键途径。为了测试p21和p16缺陷在WS中的作用，我们将WS小鼠（DKO）与或小鼠杂交，构建三敲除（p21-TKO或p16-TKO）小鼠。通过研究生存曲线、骨密度、再生组织（睾丸）和干细胞能力（肠道），我们惊讶地发现，与DKO小鼠相比，p21-TKO小鼠表现出加速的早衰，而p16-TKO小鼠则表现出衰老表型的减弱。p21-TKO小鼠组织中凋亡和细胞衰老的发生率上调，而p16-TKO小鼠中则下调。令人惊讶的是，p21-TKO小鼠组织中的细胞增殖也上调，并且与年龄匹配的DKO小鼠相比，p21-TKO小鼠没有表现出端粒缩短，尽管p16-TKO小鼠表现出端粒延长的明显增强。与这些表型一致，与DKO小鼠胚胎成纤维细胞（MEF）相比，SIRT1-PGC1途径在p16-TKO中上调，但在p21-TKO中下调。然而，与DKO MEF相比，DNA损伤反应途径在p21-TKO中高度激活，但在p16-TKO中得到挽救。这些数据表明，p21通过以适当的速率调节细胞增殖和更新来保护干细胞库，并且WS中p21的缺失激活了相当严重的DNA损伤反应（DDR），这可能导致组织稳态的异常增加。另一方面，p16通过抑制细胞增殖促进细胞衰老，p16缺陷释放了这种屏障信号而不会引起严重的DDR。
