Two faces of p53: aging and tumor suppression.
Two faces of p53: aging and tumor suppression.
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DOI：
10.1093/nar/gkm744
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发表时间：
2007
影响因子：
14.9
通讯作者：
Bhaumik, Dipa
中科院分区：
文献类型：
--
作者：
Rodier, Francis;Campisi, Judith;Bhaumik, Dipa
p53肿瘤抑制蛋白，通常被称为基因组的监护人，在哺乳动物细胞中整合各种生理信号。响应于应激信号，也许最好的研究是对DNA损伤的响应，p53在功能上变得活跃并触发瞬时细胞周期停滞、细胞死亡（凋亡）或永久细胞周期停滞（细胞衰老）。细胞凋亡和细胞衰老都是有效的肿瘤抑制机制，可不可逆地阻止受损细胞发生肿瘤转化。然而，这两个过程也可以耗尽可再生组织的增殖能力祖细胞或干细胞。这种消耗反过来会损害组织的结构和功能，这是衰老的标志。此外，尽管凋亡细胞被定义为从组织中消除，但衰老细胞可以持续存在，获得改变的功能，从而以可以促进癌症和衰老表型的方式改变组织微环境。最近的证据表明，至少在某些情况下，增加p53活性可以促进生物体衰老。在这里，我们讨论了p53作为DNA损伤反应的关键调节因子的作用，并讨论了p53如何整合DNA损伤反应的结果，以最佳地平衡肿瘤抑制和寿命。
The p53 tumor suppressor protein, often termed guardian of the genome, integrates diverse physiological signals in mammalian cells. In response to stress signals, perhaps the best studied of which is the response to DNA damage, p53 becomes functionally active and triggers either a transient cell cycle arrest, cell death (apoptosis) or permanent cell cycle arrest (cellular senescence). Both apoptosis and cellular senescence are potent tumor suppressor mechanisms that irreversibly prevent damaged cells from undergoing neoplastic transformation. However, both processes can also deplete renewable tissues of proliferation-competent progenitor or stem cells. Such depletion, in turn, can compromise the structure and function of tissues, which is a hallmark of aging. Moreover, whereas apoptotic cells are by definition eliminated from tissues, senescent cells can persist, acquire altered functions, and thus alter tissue microenvironments in ways that can promote both cancer and aging phenotypes. Recent evidence suggests that increased p53 activity can, at least under some circumstances, promote organismal aging. Here, we discuss the role of p53 as a key regulator of the DNA damage responses, and discuss how p53 integrates the outcome of the DNA damage response to optimally balance tumor suppression and longevity.