Nuclear Receptor Nur77 Regulation Of Cell Cycle And Its Application In Drug Development

Nuclear receptor Nur77 is an important member of the nuclear receptor superfamily.As the product of the immediate-early gene,it is able to respond to a variety of stimuli,including serum and various types of growth factor.Nur77 is widely involved in the physiological and pathological processes,such as cell proliferation and cell apoptosis.Our lab has reported a series of work on the journals such as Science since 2000,showing that Nur77 modulate cell apoptosis through nongenomic functions.As to its function of cell proliferation,classical transcription regulation mechanism can not explain it enoughly,whether and how some other mechanism of Nur77 can modulate the cell proliferation is still unclear.Here,we report that Nur77 underwent a dynamic relocalization during mitosis/cytokinesis,like residing at centrosome at the mitosis prophase.Then,we find that Nur77 play a critical role on modulation of mitotic progression.Knocking down Nur77 will resist the cell cycle on metaphase.During its relocalization,Nur77 were phosphorylated by cyclin-dependent kinase 1(CDK1),a key kinase regulating mitosis/cytokinesis.We also identified polo-like kinase 1(PLK1),a master regulator and coordinator of mitosis/cytokinesis,as a binding protein of phosphorylated Nur77.Cell normal proliferation and division are critical for the maintain of tissue homestasis.Abnormal of Cell proliferation and division will break the balance of cell cycle running and lead to the development of cancer and other disease.Nur77 take part in the development and progression of cancer,so it has been regarded as a potent anti-tumor drug target.It has been reported that Nur77 could induce cancer cell proliferation through promoting the cell cycle progression.And the underlying molecular events remain laregely ambiguous.Here,this mechanism will provide a new stategy for development of anti-tumor drug.2017,our lab reported that Celastrol is a ligand of Nur77.Due to the toxic and side effect of Celastrol,we design and product a series of Celastrol derivatives.Luckily,we find a compound,which is selected by screening the celastrol derivates,can arrest the cell cycle on metaphase strongly by targeting Nur77,and induce cancer cell apoptosis These results reveal a innovative role of Nur77 at mitosis,which has important significance in developing Nur77 based cancer therapeutics.