PDF(Pubmed)
Abstract：
Full-length p53 (p53α) plays a pivotal role in maintaining genomic integrity and preventing tumor development. Over the years, p53 was found to exist in various isoforms, which are generated through alternative splicing, alternative initiation of translation, and internal ribosome entry site. p53 isoforms, either C-terminally altered or N-terminally truncated, exhibit distinct biological roles compared to p53α, and have significant implications for tumor development and therapy resistance. Due to a lack of part and/or complete C- or N-terminal domains, ectopic expression of some p53 isoforms failed to induce expression of canonical transcriptional targets of p53α like CDKN1A or MDM2, even though they may bind their promoters. Yet, p53 isoforms like Δ40p53α still activate subsets of targets including MDM2 and BAX. Furthermore, certain p53 isoforms transactivate even novel targets compared to p53α. More recently, non-canonical functions of p53α in DNA repair and of different isoforms in DNA replication unrelated to transcriptional activities were discovered, amplifying the potential of p53 as a master regulator of physiological and tumor suppressor functions in human cells. Both regarding canonical and non-canonical functions, alternative p53 isoforms frequently exert dominant negative effects on p53α and its partners, which is modified by the relative isoform levels. Underlying mechanisms include hetero-oligomerization, changes in subcellular localization, and aggregation. These processes ultimately influence the net activities of p53α and give rise to diverse cellular outcomes. Biological roles of p53 isoforms have implications for tumor development and cancer therapy resistance. Dysregulated expression of isoforms has been observed in various cancer types and is associated with different clinical outcomes. In conclusion, p53 isoforms have expanded our understanding of the complex regulatory network involving p53 in tumors. Unraveling the mechanisms underlying the biological roles of p53 isoforms provides new avenues for studies aiming at a better understanding of tumor development and developing therapeutic interventions to overcome resistance.
摘要：
全长p53（p53α）在维持基因组完整性和预防肿瘤发展中起关键作用。多年来,发现p53以各种亚型存在，它们是通过交替拼接产生的，替代翻译的开始，和内部核糖体进入位点。p53亚型，C端改变或N端截短，与p53α相比，表现出不同的生物学作用，并对肿瘤的发展和治疗耐药具有重要意义。由于缺乏部分和/或完整的C-或N-末端结构域，某些p53亚型的异位表达未能诱导p53α的典型转录靶标如CDKN1A或MDM2的表达，即使它们可能结合其启动子。然而，p53同种型如Δ40p53α仍然激活包括MDM2和BAX的靶标的子集。此外，与p53α相比，某些p53同工型甚至可以激活新的靶标。最近,发现了p53α在DNA修复中的非规范功能和与转录活性无关的DNA复制中的不同同工型，放大p53作为人细胞中生理和肿瘤抑制功能的主要调节因子的潜力。关于规范和非规范函数，替代p53亚型经常对p53α及其配偶体发挥显性负效应，由相对同工型水平修饰。潜在机制包括异源寡聚体化，亚细胞定位的变化，和聚合。这些过程最终影响p53α的净活性并产生不同的细胞结果。p53同工型的生物学作用对肿瘤发展和癌症治疗抗性有影响。已经在各种癌症类型中观察到同工型的表达失调,并且与不同的临床结果相关。总之,p53亚型扩大了我们对肿瘤中涉及p53的复杂调控网络的理解。揭示p53同工型生物学作用的潜在机制为旨在更好地了解肿瘤发展和开发治疗干预措施以克服耐药性的研究提供了新的途径。
