Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence |
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Authors: | Cosme-Blanco Wilfredo Shen Mei-Feng Lazar Alexander J F Pathak Sen Lozano Guillermina Multani Asha S Chang Sandy |
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Affiliation: | Department of Cancer Genetics, The MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. |
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Abstract: | 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. |
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