p53 and Notch signaling in chronic lymphocytic leukemia: clues to identifying novel therapeutic strategies
p53 and Notch signaling in chronic lymphocytic leukemia: clues to identifying novel therapeutic strategies
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DOI：
10.1038/leu.2011.103
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发表时间：
2011-05
期刊：
影响因子：
11.4
通讯作者：
R. Wickremasinghe;A. Prentice;A. Steele
中科院分区：
文献类型：
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作者：
R. Wickremasinghe;A. Prentice;A. Steele
p53肿瘤抑制蛋白在慢性淋巴细胞白血病（CLL）细胞凋亡诱导中起关键作用。p53通路内的异常可识别预后不良的患者亚群。本文综述了近年来对p53水平调控机制的研究进展，以及p53在细胞周期和凋亡调控中的作用。p53介导细胞凋亡的经典模型强调促凋亡基因的转录激活。相反，一个新的模型强调p53的非转录作用是诱导凋亡的主要途径，而其转录臂主要上调抗凋亡基因，从而提供了限制凋亡的负反馈机制。进一步的研究已经确定Notch通路是p53诱导的抗凋亡的候选机制。与经典模型相反，新模型预测，药物抑制p53的转录功能或Notch信号通路将增强细胞毒性药物对细胞凋亡的诱导。基于新模型的治疗策略，我们在这里首次回顾，可能会显著增强细胞毒性药物在CLL和其他恶性肿瘤中的抗肿瘤作用。
The p53 tumor suppressor protein has a key role in the induction of apoptosis of chronic lymphocytic leukemia (CLL) cells. Abnormalities within the p53 pathway identify a subset of patients with a poor prognosis. This review describes recent advances in understanding the mechanisms that regulate p53 levels and the role of p53 in the control of the cell cycle and of apoptosis. The classical model of p53-mediated apoptosis emphasizes the transcriptional activation of proapoptotic genes. In contrast, a novel model emphasizes p53's non-transcriptional actions as the major route of apoptosis induction, whereas its transcriptional arm predominantly upregulates antiapoptotic genes, thus providing a negative feedback mechanism that limits apoptosis. Further studies have identified the Notch pathway as a candidate p53-induced antiapoptotic mechanism. In contrast to the classical model, the novel model predicts that pharmacological inhibition of p53's transcriptional function or of the Notch signaling pathway will augment apoptosis induction by cytotoxic agents. Therapeutic strategies based on the novel model, which we review here for the first time, may significantly augment the antitumor actions of cytotoxic agents in CLL and in other malignancies.