Department of Biochemistry, School of Medicine, and Institute for Tumour Research, Chungbuk National University, Cheongju, South Korea.
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
J Mol Cell Biol. 2019 Mar 1;11(3):224-230. doi: 10.1093/jmcb/mjy076.
RUNX genes belong to a three-membered family of transcription factors, which are well established as master regulators of development. Of them, aberrations in RUNX3 expression are frequently observed in human malignancies primarily due to epigenetic silencing, which is often overlooked. At the G1 phase of the cell cycle, RUNX3 regulates the restriction (R)-point, a mechanism that decides cell cycle entry. Deregulation at the R-point or loss of RUNX3 results in premature entry into S phase, leading to a proliferative advantage. Inactivation of Runx1 and Runx2 induce immortalization of mouse embryo fibroblast. As a consequence, RUNX loss induces pre-cancerous lesions independent of oncogene activation. p53 is the most extensively studied tumour suppressor. p53 plays an important role to prevent tumour progression but not tumour initiation. Therefore, upon oncogene activation, early inactivation of RUNX genes and subsequent mutation of p53 appear to result in tumour initiation and progression. Recently, transcription-independent DNA repairing roles of RUNX3 and p53 are emerging. Being evolutionarily old genes, it appears that the primordial function of p53 is to protect genome integrity, a function that likely extends to the RUNX gene as well. In this review, we examine the mechanism and sequence of actions of these tumour suppressors in detail.
RUNX 基因属于转录因子的三成员家族，它们作为发育的主要调节因子已得到充分证实。其中，RUNX3 表达的异常经常在人类恶性肿瘤中观察到，主要是由于表观遗传沉默，这常常被忽视。在细胞周期的 G1 期，RUNX3 调节限制（R）点，这是决定细胞周期进入的机制。R 点的失调或 RUNX3 的缺失导致过早进入 S 期，导致增殖优势。Runx1 和 Runx2 的失活诱导小鼠胚胎成纤维细胞的永生化。因此，RUNX 的失活导致癌前病变，而与癌基因激活无关。p53 是研究最广泛的肿瘤抑制因子。p53 在防止肿瘤进展方面起着重要作用，但不能防止肿瘤起始。因此，在癌基因激活后，RUNX 基因的早期失活和随后的 p53 突变似乎导致肿瘤起始和进展。最近，RUNX3 和 p53 的转录独立的 DNA 修复作用正在出现。作为古老的基因，p53 的原始功能似乎是保护基因组完整性，这一功能可能也延伸到 RUNX 基因。在这篇综述中，我们详细检查了这些肿瘤抑制因子的作用机制和作用顺序。
