2. Academic Validation
  3. Centrosomal Localization of RXRα Promotes PLK1 Activation and Mitotic Progression and Constitutes a Tumor Vulnerability

Centrosomal Localization of RXRα Promotes PLK1 Activation and Mitotic Progression and Constitutes a Tumor Vulnerability

  • Dev Cell. 2020 Dec 21;55(6):707-722.e9. doi: 10.1016/j.devcel.2020.11.012.
Guobin Xie 1,  Yuqi Zhou 2,  Xuhuang Tu 1,  Xiaohong Ye 1,  Lin Xu 1,  Zhijian Xiao 1,  Qiqiang Wang 1,  Xin Wang 1,  Mingxuan Du 1,  Ziwen Chen 2,  Xiaoqin Chi 3,  Xiaoli Zhang 1,  Ji Xia 1,  Xiaowei Zhang 1,  Yunxia Zhou 1,  Zongxi Li 1,  Chengrong Xie 3,  Luoyan Sheng 1,  Zhiping Zeng 1,  Hu Zhou 1,  Zhenyu Yin 3,  Ying Su 2,  Yang Xu 1,  Xiao-Kun Zhang 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China.
  • 2 School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China; NucMito Pharmaceuticals Co. Ltd., Xiamen 361101, Fujian, China.
  • 3 Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital Xiamen University, Xiamen 361004, Fujian, China.
  • 4 School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China. Electronic address: xkzhang@xmu.edu.cn.
PMID: 33321102 DOI: 10.1016/j.devcel.2020.11.012
Abstract

Retinoid X receptor alpha (RXRα), a nuclear receptor of transcription factor, controls various physiological and pathological pathways including cellular growth, proliferation, differentiation, and Apoptosis. Here, we report that RXRα is phosphorylated at its N-terminal A/B domain by cyclin-dependent kinase 1 (CDK1) at the onset of mitosis, triggering its translocation to the centrosome, where phosphorylated-RXRα (p-RXRα) interacts with polo-like kinase 1 (PLK1) through its N-terminal A/B domain by a unique mechanism. The interaction promotes PLK1 activation, centrosome maturation, and mitotic progression. Levels of p-RXRα are abnormally elevated in Cancer cell lines, during carcinogenesis in Animals, and in clinical tumor tissues. An RXRα ligand XS060, which specifically inhibits p-RXRα/PLK1 interaction but not RXRα heterodimerization, promotes mitotic arrest and catastrophe in a tumor-specific manner. These findings unravel a transcription-independent action of RXRα at the centrosome during mitosis and identify p-RXRα as a tumor-specific vulnerability for developing mitotic drugs with improved therapeutic index.

Keywords

Cdk1; PLK1; RXRα; RXRα ligand; RXRα phosphorylation; catastrophe; centrosome; mitosis; nuclear receptor; tumor vulnerability.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149085
    98.67%, RXRα Antagonist