Shen Kate C, Heng Henry, Wang Yaolin, Lu Shu, Liu Guo, Deng Chu-Xia, Brooks S C, Wang Y Alan
Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201, USA.
Cancer Res. 2005 Oct 1;65(19):8747-53. doi: 10.1158/0008-5472.CAN-05-1471.
The DNA damage checkpoint protein kinase mutated in ataxia telangiectasia (ATM) is involved in sensing and transducing DNA damage signals by phosphorylating and activating downstream target proteins that are implicated in the regulation of cell cycle progression and DNA repair. Atm-/- cells are defective in cellular proliferation mediated by the Arf/p53/p21 pathway. In this report, we show that increased expression of p21 (also known as Waf1 or CDKN1a) in Atm-/- cells serves as a cellular defense mechanism to suppress further chromosomal instability (CIN) and tumor development because Atm-/- p21-/- mice are predisposed to carcinomas and sarcomas with intratumoral heterogeneity. It was found that Atm-deficient cells are defective in metaphase-anaphase transition leading to abnormal karyokinesis. Moreover, Atm-/- p21-/- primary embryonic fibroblasts exhibit increased CIN compared with either Atm-/- or p21-/- cells. The increased CIN is manifested at the cellular level by increased chromatid breaks and elevated aneuploid genome in Atm-/- p21-/- cells. Finally, we showed that the role of p21 in a CIN background induced by loss of Atm is to suppress numerical CIN but not structural CIN. Our data suggest that the development of aneuploidy precedes tumor formation and implicates p21 as a major tumor suppressor in a genome instability background.
共济失调毛细血管扩张症中发生突变的DNA损伤检查点蛋白激酶（ATM），通过磷酸化并激活下游靶蛋白来参与DNA损伤信号的感知和转导，这些靶蛋白与细胞周期进程和DNA修复的调控有关。Atm基因敲除细胞在由Arf/p53/p21途径介导的细胞增殖方面存在缺陷。在本报告中，我们表明Atm基因敲除细胞中p21（也称为Waf1或CDKN1a）表达的增加，作为一种细胞防御机制，可抑制进一步的染色体不稳定（CIN）和肿瘤发展，因为Atm基因敲除/p21基因敲除小鼠易患具有肿瘤内异质性的癌和肉瘤。研究发现，Atm缺陷细胞在中期 - 后期转换方面存在缺陷，导致核分裂异常。此外，与Atm基因敲除细胞或p21基因敲除细胞相比，Atm基因敲除/p21基因敲除的原代胚胎成纤维细胞表现出更高的CIN。Atm基因敲除/p21基因敲除细胞中增加的CIN在细胞水平上表现为染色单体断裂增加和非整倍体基因组升高。最后，我们表明p21在由Atm缺失诱导的CIN背景中的作用是抑制数字CIN而非结构CIN。我们的数据表明，非整倍体的发展先于肿瘤形成，并表明p21在基因组不稳定背景下是一种主要的肿瘤抑制因子。
