Komarova E A, Gudkov A V
Department of Molecular Genetics, University of Illinois at Chicago 60607, USA.
Semin Cancer Biol. 1998;8(5):389-400. doi: 10.1006/scbi.1998.0101.
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.
传统上，p53的功能是在其肿瘤抑制活性的背景下被看待的。事实上，p53依赖的生长停滞和凋亡，在对多种刺激的反应中发生，通过消除潜在的肿瘤前体来保护机体免受癌症侵害。然而，p53的相同功能可能会因与抗肿瘤治疗相关的基因毒性应激而导致正常组织的严重损伤。这使得p53成为治疗性抑制的潜在靶点，目的是使正常组织免受癌症治疗副作用的影响。我们分析了关于p53在体内基因毒性应激的急性和长期后果中作用的累积信息。对p53野生型和p53缺陷型小鼠的比较表明，事实上，p53决定了辐射敏感组织在γ射线照射后不久发生的大量凋亡。凋亡位点与p53 mRNA表达的组织特异性模式相匹配，表明p53在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，辐射诱导的分化细胞和干细胞死亡强烈依赖于p53，这表明抑制p53将减少损伤并促进抗癌治疗后造血功能更快恢复。然而，p53并不影响辐射敏感上皮细胞的恢复，因为与分化细胞相比，它们的干细胞以p53非依赖的方式死亡。结合p53在正常发育中的功能，讨论了在癌症治疗和其他应激条件下治疗性抑制p53的有效性和潜在并发症。
