Ligand-dependent Interaction Of RARα/RXRα Heterodimer With PLK1 Modulates Mitotic Progression

The mitotic progression of eukaryote cells is crucial for the development and maintenance of tissue homeostasis.In normal cells,mitosis is highly regulated and coordinated,but it is extremely vulnerable to perturbations.Uncontrolled mitosis is the main reason for tumorigenesis and rapid tumor cell proliferation.During mitosis,the nuclear envelope breaks,chromosomes condense,transcription factors are dissociated from the condensed chromosomes,and the gene transcription program is silent.Where are the nuclear transcription factors and what do they do during mitosis remains largely unknown.As the main recipients of vitamin A signals,the retinoic acid receptor-alpha(RARα)and the retinoic acid X receptor-alpha(RXRα)play important roles in vertebrate embryonic development,growth and homeostasis.Molecules targeting RARa and RXRa have been used in clinical for cancer treatments,but the mechanism of treatments need to further explore.Previous study from our laboratory revealed that RXRa is phosphorylated by cyclin-dependent kinase 1(CDK1)at the onset of mitosis,resulting in its translocation to the centrosome where the phosphorylated RXRa interacts with the polo-like kinase 1(PLK1).The interaction of phosphorylated RXRα with PLK1 regulates the maturation and function of the centrosome,promoting mitotic progression.Here we report that the heterodimer formed by RXRa and RARa can also bind to PLK1 in a RARa ligand dependent manner.In studying the subcellular localization of RARa during mitosis,we found that RARa translocates to the centrosome together with RXRa in the presence of all-trans-retinoic acid(ATRA),a RARα ligand.In addition,we found that RARa resides at the centromere.Knocking down RARa by siRNA approach impairs the microtubule nucleation from the centrosome,increases the rate of chromosome misalignment,and hence mitotic arrest.Finally,we identified MM11384,a small molecule that activates the transcription activity of RARα,as a potent inducer of the interaction between RARα/RXRα and PLK1.Treatment of cells with MM11384 results in their arrest at G2/M phase,followed by apoptosis.In conclusion,our results showed that the RARα/RXRa heterodimer plays an important role in regulating mitotic progression in a RARa ligand dependent manner,providing new strategies for developing RARα-based drugs targeting mitosis.