Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands.
Int J Mol Sci. 2021 May 20;22(10):5377. doi: 10.3390/ijms22105377.
The P53 pathway is the most important cellular pathway to maintain genomic and cellular integrity, both in embryonic and non-embryonic cells. Stress signals induce its activation, initiating autophagy or cell cycle arrest to enable DNA repair. The persistence of these signals causes either senescence or apoptosis. Over 50% of all solid tumors harbor mutations in that inactivate the pathway. The remaining cancers are suggested to harbor mutations in genes that regulate the P53 pathway such as its inhibitors Mouse Double Minute 2 and 4 (MDM2 and MDM4, respectively). Many reviews have already been dedicated to P53, MDM2, and MDM4, while this review additionally focuses on the other factors that can deregulate P53 signaling. We discuss that P14 (ARF) functions as a negative regulator of MDM2, explaining the frequent loss of ARF detected in cancers. The long non-coding RNA Antisense Non-coding RNA in the Locus (ANRIL) is encoded on the same locus as , inhibiting ARF expression, thus contributing to the process of tumorigenesis. Mutations in tripartite motif (TRIM) proteins deregulate P53 signaling through their ubiquitin ligase activity. Several microRNAs (miRNAs) inactivate the P53 pathway through inhibition of translation. CCCTC-binding factor (CTCF) maintains an open chromatin structure at the locus, explaining its inactivation of CTCF during tumorigenesis. P21, a downstream effector of P53, has been found to be deregulated in different tumor types. This review provides a comprehensive overview of these factors that are known to deregulate the P53 pathway in both somatic and embryonic cells, as well as their malignant counterparts (i.e., somatic and germ cell tumors). It provides insights into which aspects still need to be unraveled to grasp their contribution to tumorigenesis, putatively leading to novel targets for effective cancer therapies.
P53 通路是维持胚胎和非胚胎细胞基因组和细胞完整性的最重要的细胞通路。应激信号诱导其激活，启动自噬或细胞周期停滞以实现 DNA 修复。这些信号的持续存在会导致衰老或细胞凋亡。超过 50%的所有实体瘤都携带有失活该通路的 基因突变。其余的癌症被认为携带有调节 P53 通路的基因的突变，例如其抑制剂 Mouse Double Minute 2 和 4（MDM2 和 MDM4，分别）。已经有许多关于 P53、MDM2 和 MDM4 的综述，而本综述还重点关注了其他可能使 P53 信号通路失稳的因素。我们讨论了 P14（ARF）作为 MDM2 的负调节剂的功能，解释了在癌症中经常检测到的 ARF 缺失。长非编码 RNA Antisense Non-coding RNA in the Locus（ANRIL）位于 基因的同一位置，抑制 ARF 的表达，从而促进肿瘤发生的过程。三部分基序（TRIM）蛋白的突变通过其泛素连接酶活性调节 P53 信号。几种 microRNAs（miRNAs）通过抑制翻译使 P53 通路失活。CCCTC 结合因子（CTCF）在 基因座保持开放染色质结构，解释了其在肿瘤发生过程中对 CTCF 的失活。P53 的下游效应物 P21 在不同的肿瘤类型中被发现失调。本综述提供了这些已知在体细胞和胚胎细胞以及它们的恶性对应物（即体细胞和生殖细胞肿瘤）中使 P53 通路失稳的因素的全面概述，以及它们对肿瘤发生的潜在贡献，为有效的癌症治疗提供了新的潜在靶点。
