Cosme-Blanco Wilfredo, Shen Mei-Feng, Lazar Alexander J F, Pathak Sen, Lozano Guillermina, Multani Asha S, Chang Sandy
Department of Cancer Genetics, The MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
EMBO Rep. 2007 May;8(5):497-503. doi: 10.1038/sj.embor.7400937. Epub 2007 Mar 30.
Dysfunctional telomeres induce p53-dependent cellular senescence and apoptosis, but it is not known which function is more important for tumour suppression in vivo. We used the p53 ( R172P ) knock-in mouse, which is unable to induce apoptosis but retains intact cell-cycle arrest and cellular senescence pathways, to show that spontaneous tumorigenesis is potently repressed in Terc -/- p53 ( R172P ) mice. Tumour suppression is accompanied by global induction of p53, p21 and the senescence marker senescence-associated-beta-galactosidase. By contrast, cellular senescence was unable to suppress chemically induced skin carcinomas. These results indicate that suppression of spontaneous tumorigenesis by dysfunctional telomeres requires the activation of the p53-dependent cellular senescence pathway.
功能失调的端粒可诱导p53依赖的细胞衰老和凋亡，但目前尚不清楚哪种功能对体内肿瘤抑制更为重要。我们使用了p53（R172P）基因敲入小鼠，该小鼠无法诱导凋亡，但保留了完整的细胞周期阻滞和细胞衰老途径，结果显示在Terc-/- p53（R172P）小鼠中，自发肿瘤发生受到有效抑制。肿瘤抑制伴随着p53、p21以及衰老标志物衰老相关β-半乳糖苷酶的整体诱导。相比之下，细胞衰老无法抑制化学诱导的皮肤癌。这些结果表明，功能失调的端粒对自发肿瘤发生的抑制需要激活p53依赖的细胞衰老途径。
