Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice.
Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice.
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DOI：
10.18632/oncotarget.4956
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发表时间：
2015-07-20
期刊：
影响因子：
--
通讯作者：
Lane DP
中科院分区：
文献类型：
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作者：
Goh AM;Xue Y;Leushacke M;Li L;Wong JS;Chiam PC;Rahmat SA;Mann MB;Mann KM;Barker N;Lozano G;Terzian T;Lane DP
肿瘤抑制因子p53主要在蛋白水平受到调控。在正常组织中，它的水平通过特定的E3连接酶和泛素蛋白体途径维持在非常低的水平。突变的p53蛋白参与转化、转移和耐药。在肿瘤中可以发现高水平的p53突变体，而在人类皮肤的病理正常细胞中也曾报道过p53突变体的积累。我们首次证明，在p53突变敲入小鼠模型中，在明显正常的细胞中可以检测到类似的突变p53水平升高。事实上，在小肠中，突变型p53以依赖于基因剂量和细胞类型的方式自发积累。突变型p53蛋白的调控与野生型p53相似，在电离辐射或Mdm2抑制剂诱导后可迅速积累，但突变型p53蛋白的清除速度远慢于野生型p53。该蛋白在小鼠小肠内的积累仅限于循环区、隐窝基柱状细胞区和增殖区，并随着细胞分化和退出细胞周期而丢失。Mdm2的缺失导致p53的表达水平更高，但p53仍然局限于小肠中的增殖细胞。因此，这些p53突变小鼠的小肠是一个实验系统，我们可以解剖导致p53积累的分子途径，这对癌症的预防和治疗具有重要意义。
The tumour suppressor p53 is regulated primarily at the protein level. In normal tissues its levels are maintained at a very low level by the action of specific E3 ligases and the ubiquitin proteosome pathway. The mutant p53 protein contributes to transformation, metastasis and drug resistance. High levels of mutant p53 can be found in tumours and the accumulation of mutant p53 has previously been reported in pathologically normal cells in human skin. We show for the first time that similarly elevated levels of mutant p53 can be detected in apparently normal cells in a mutant p53 knock-in mouse model. In fact, in the small intestine, mutant p53 spontaneously accumulates in a manner dependent on gene dosage and cell type. Mutant p53 protein is regulated similarly to wild type p53, which can accumulate rapidly after induction by ionising radiation or Mdm2 inhibitors, however, the clearance of mutant p53 protein is much slower than wild type p53. The accumulation of the protein in the murine small intestine is limited to the cycling, crypt base columnar cells and proliferative zone and is lost as the cells differentiate and exit the cell cycle. Loss of Mdm2 results in even higher levels of p53 expression but p53 is still restricted to proliferating cells in the small intestine. Therefore, the small intestine of these p53 mutant mice is an experimental system in which we can dissect the molecular pathways leading to p53 accumulation, which has important implications for cancer prevention and therapy.