Could p53 be a target for therapeutic suppression?
Could p53 be a target for therapeutic suppression?
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DOI：
10.1006/scbi.1998.0101
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发表时间：
1998-10-01
影响因子：
14.5
通讯作者：
Gudkov, AV
中科院分区：
文献类型：
--
作者：
Komarova, EA;Gudkov, AV
p53的功能传统上被认为是它的肿瘤抑制活性。事实上，p53依赖的生长停滞和细胞凋亡是对各种刺激的反应，通过消除潜在的肿瘤前体来保护生物体免受癌症的侵害。然而，p53的相同功能可以决定与抗肿瘤治疗相关的基因毒性应激对正常组织的严重损伤。这使得p53成为治疗抑制的潜在靶点，目的是将正常组织从癌症治疗的副作用中拯救出来。我们分析了积累的关于p53在体内基因毒性应激的急性和长期后果中的作用的信息。p53野生型和p53缺失型小鼠的比较表明，p53实际上决定了放射敏感组织在γ辐照后不久发生的大量凋亡。凋亡位点与p53 mRNA的组织特异性表达模式相匹配，表明p53 mRNA水平的调控是组织急性放射敏感性的决定因素。在造血系统中，放射诱导的分化细胞和干细胞的死亡都强烈依赖于p53，这表明抑制p53可以减少损伤，促进抗癌治疗后造血功能的更快恢复。然而，p53不影响放射敏感上皮的恢复，因为它们的干细胞与分化细胞不同，以不依赖p53的方式死亡。本文讨论了在癌症治疗和其他应激条件下抑制p53的有效性和潜在的并发症，以及p53在正常发育中的功能。
The function of p53 has been traditionally viewed in the context of its tumor suppressor activity. In fact, the p53-dependent growth arrest and apoptosis, occurring in response to a variety of stimuli, act to protect the organism from cancer by eliminating potential tumor precursors. However, the same functions of p53 could determine severe damage of normal tissues as a consequence of genotoxic stress associated with anti-tumor therapy. This makes p53 a potential target for therapeutic suppression with the purpose of rescuing normal tissues from the side effects of cancer treatment. We analyze the accumulated information regarding the role of p53 in acute and long-term consequences of genotoxic stress in vivo. Comparison of p53 wild type and p53-deficient mice indicates that p53, in fact, determines massive apoptosis occurring shortly after gamma irradiation in radiosensitive tissues. Sites of apoptosis match the tissue-specific pattern of p53 mRNA expression indicating that p53 regulation at mRNA level is a determinant of acute radiosensitivity of tissues. In the hematopoietic system, radiation-induced death of both differentiating and stem cells strongly depends on p53 suggesting that p53 suppression would decrease damage and promote faster recovery of hematopoiesis after anti-cancer therapy. However, p53: does not effect the recovery of radiosensitive epithelia since their stem cells, in contrast to differentiating cells, die in a p53-independent manner. The validity and potential complications of therapeutic suppression of p53 in cancer treatment and under other stressful conditions are discussed in relation to the p53 functions in normal development.