Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
Leuk Lymphoma. 2012 Nov;53(11):2116-29. doi: 10.3109/10428194.2012.684348. Epub 2012 May 21.
p53, mutated in over half of human cancers and about 13% of all hematological malignancies, maintains genomic integrity and triggers cellular senescence and apoptosis of damaged cells. In contrast to p53, the homologs p73 and p63 play critical roles in development of the central nervous system and skin/limbs, respectively. Moreover, dependent on the context they can exert tumor suppressor activities that cooperate with p53. Unlike p53, p73 and p63 are rarely mutated in cancers. Instead, up-regulation of the anti-apoptotic dominant-negative ΔNp73 and ΔNp63 isoforms is the most frequent abnormality in solid cancers. In hematological malignancies the most frequent p73 defect is promoter methylation and loss of expression, associated with unfavorable clinical outcomes. This suggests an essential tumor suppressor role of p73 in blood cells, also supported by genetic mouse models. Many therapeutic approaches aiming to restore p73 activity are currently being investigated. In contrast, the most frequent p63 abnormality is protein overexpression, associated with higher disease grade and poorer prognosis. Surprisingly, although available data are still scarce, the emerging picture is up-regulation of transactivation-competent TAp63 isoforms, suggesting a tumor-promoting role in this context.
p53 在超过一半的人类癌症和大约 13%的所有血液系统恶性肿瘤中发生突变，它维持基因组完整性，并触发受损细胞的细胞衰老和凋亡。与 p53 相反，同源物 p73 和 p63 分别在中枢神经系统和皮肤/四肢的发育中发挥关键作用。此外，它们可以根据具体情况发挥肿瘤抑制活性，与 p53 合作。与 p53 不同，p73 和 p63 在癌症中很少发生突变。相反，抗凋亡显性负ΔNp73 和 ΔNp63 异构体的上调是实体瘤中最常见的异常。在血液系统恶性肿瘤中，p73 最常见的缺陷是启动子甲基化和表达缺失，与不良的临床结局相关。这表明 p73 在血细胞中具有重要的肿瘤抑制作用，这也得到了遗传小鼠模型的支持。目前正在研究许多旨在恢复 p73 活性的治疗方法。相比之下，p63 最常见的异常是蛋白过表达，与更高的疾病分级和更差的预后相关。令人惊讶的是，尽管可用数据仍然有限，但新兴的图景是转录激活有效 TAp63 异构体的上调，这表明在这种情况下具有促进肿瘤的作用。
