Department of Maternal-Fetal Biology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan.
Mol Cell Biol. 2010 May;30(9):2090-104. doi: 10.1128/MCB.01318-09. Epub 2010 Feb 16.
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.
细胞衰老（Cellular senescence）是一种不可逆的生长停滞，被认为是肿瘤发展的天然屏障。与端粒缩短一样，某些染色体完整性缺陷也可能引发衰老；然而，着丝粒蛋白在调节衰老状态的决定中所起的作用尚待确定。我们检测了衰老的人原代成纤维细胞中的染色质结构，发现 CENP-A 蛋白水平在衰老细胞中降低。衰老相关的 CENP-A 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 RNA 强制降低 CENP-A 被发现会导致人原代成纤维细胞过早衰老。这种过早衰老依赖于肿瘤抑制因子 p53，但不依赖于 p16(INK4a)-Rb;p53 缺陷细胞中 CENP-A 的耗竭会导致染色体错误分离的异常有丝分裂。我们提出，由于 CENP-A 减少而导致的 p53 依赖性衰老作为一种“自我防御机制”，可防止着丝粒缺陷细胞进行有丝分裂增殖，从而潜在地导致非整倍体细胞的大量产生。
