CENP-A Reduction Induces a p53-Dependent Cellular Senescence Response To Protect Cells from Executing Defective Mitoses
CENP-A Reduction Induces a p53-Dependent Cellular Senescence Response To Protect Cells from Executing Defective Mitoses
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DOI：
10.1128/mcb.01318-09
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发表时间：
2010-05-01
影响因子：
5.3
通讯作者：
Saitoh, Shigeaki
中科院分区：
文献类型：
--
作者：
Maehara, Kayoko;Takahashi, Kohta;Saitoh, Shigeaki
细胞衰老是一种不可逆转的生长停滞，被认为是肿瘤发展的天然屏障。与端粒缩短一样，染色体完整性的某些缺陷也会引发衰老；然而，着丝粒蛋白在调节衰老状态的承诺方面的作用仍有待确定。我们研究了衰老的人原代成纤维细胞的染色质结构，发现衰老的细胞中CENP-A蛋白水平降低。CENP-A的衰老相关减少是由转录和翻译后控制引起的。令人惊讶的是，通过短发夹状RNA强制降低CENP-A被发现会导致人类原代成纤维细胞过早衰老。这种早衰依赖于肿瘤抑制基因P53，但不依赖于p16(INK4a)-Rb；在P53缺失的细胞中，CENP-A的缺失导致异常有丝分裂和染色体错误分离。我们认为，CENP-A减少引起的P53依赖的衰老是一种“自卫机制”，可以防止着丝粒缺陷细胞进行有丝分裂增殖，从而有可能导致大量非整倍体细胞的产生。
Cellular senescence is an irreversible growth arrest and is presumed to be a natural barrier to tumor development. Like telomere shortening, certain defects in chromosome integrity can trigger senescence; however, the roles of centromere proteins in regulating commitment to the senescent state remains to be established. We examined chromatin structure in senescent human primary fibroblasts and found that CENP-A protein levels are diminished in senescent cells. Senescence-associated reduction of CENP-A is caused by transcriptional and posttranslational control. Surprisingly, forced reduction of CENP-A by short-hairpin RNA was found to cause premature senescence in human primary fibroblasts. This premature senescence is dependent on a tumor suppressor, p53, but not on p16(INK4a)-Rb; the depletion of CENP-A in p53-deficient cells results in aberrant mitosis with chromosome missegregation. We propose that p53-dependent senescence that arises from CENP-A reduction acts as a "self-defense mechanism" to prevent centromere-defective cells from undergoing mitotic proliferation that potentially leads to massive generation of aneuploid cells.