Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, Beijing, 100044, China.
Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
J Exp Clin Cancer Res. 2018 Feb 13;37(1):28. doi: 10.1186/s13046-018-0693-7.
Identification of novel MDM2 or p53 binding proteins may reveal undefined oncogenes, tumor suppressors, signaling pathways and possible treatment targets.
By means of immunoprecipitation and Mass Spectrometry analysis, we aimed to identify novel regulators of the MDM2-p53 pathway. We further clarified the impact of MYL6B on the p53 protein level and on the process of apoptosis. We also investigated the role of MYL6B in hepatocellular carcinoma by clone formation assay and by determining the correlation between its expression and prognosis of HCC patients.
We identified a novel MDM2 and p53 binding protein, MYL6B. It is a myosin light chain that could bind myosin II heavy chains to form non-muscle myosin II holoenzymes (NMII). We found that MYL6B could facilitate the binding of MDM2 to p53, which consequently promotes the ubiquitination and degradation of p53 protein. We further proved that MYL6B exerts the suppression effect on p53 as part of NMII holoenzymes because inhibiting the ATPase activity of myosin II heavy chain largely blocked this effect. We also discovered that MYL6B is overexpressed in HCC tissues and linked to the bad prognosis of HCC patients. Knocking out of MYL6B dramatically suppressed the clonogenic ability and increased the apoptosis level of HCC cell lines.
To summary, our results demonstrate that MYL6B is a putative tumor driver gene in HCC which could promote the degradation of p53 by enhancing its' MDM2-mediated ubiquitination.
鉴定新的 MDM2 或 p53 结合蛋白可能揭示未定义的癌基因、肿瘤抑制因子、信号通路和可能的治疗靶点。
通过免疫沉淀和质谱分析，我们旨在鉴定新的 MDM2-p53 通路调节剂。我们进一步阐明了 MYL6B 对 p53 蛋白水平和细胞凋亡过程的影响。我们还通过克隆形成实验和确定其表达与 HCC 患者预后之间的相关性，研究了 MYL6B 在肝细胞癌中的作用。
我们鉴定出一种新的 MDM2 和 p53 结合蛋白，MYL6B。它是一种肌球蛋白轻链，可以将肌球蛋白 II 重链结合形成非肌球蛋白 II 全酶（NMII）。我们发现 MYL6B 可以促进 MDM2 与 p53 的结合，从而促进 p53 蛋白的泛素化和降解。我们进一步证明，MYL6B 作为 NMII 全酶的一部分发挥对 p53 的抑制作用，因为抑制肌球蛋白 II 重链的 ATP 酶活性在很大程度上阻断了这种作用。我们还发现 MYL6B 在 HCC 组织中过表达，并与 HCC 患者的不良预后相关。敲除 MYL6B 可显著抑制 HCC 细胞系的集落形成能力并增加细胞凋亡水平。
总之，我们的结果表明，MYL6B 是 HCC 中的一个潜在的肿瘤驱动基因，它可以通过增强其 MDM2 介导的泛素化来促进 p53 的降解。
