Myocyte enhancer factor 2D (MEF2D) is predominantly expressed in the nucleus and associated with cell growth, differentiation, survival and apoptosis. Previous studies verified that phosphorylation at different amino acids determined MEF2's transcriptional activity which was essential in regulating downstream target genes expression. What regulates phosphorylation of MEF2D and affects its function has not been fully elucidated. Here, we uncovered that dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), a kinase critical in Down's syndrome pathogenesis, directly bound to and phosphorylated MEF2D at Ser251 in vitro. Phosphorylation of MEF2D by DYRK1A significantly increased MEF2D protein level but attenuated its transcriptional activity, which resulted in decreased transcriptions of MEF2D target genes. Phosphorylation mutated Ser251A MEF2D exhibited enhanced transcriptional activity compared with wild type MEF2D. MEF2D and DYRK1A were observed co-localized in HEK293 and U87MG cells. Moreover, DYRK1A-mediated MEF2D phosphorylation in vitro might influence its nuclear export upon subcellular fractionation, which partially explained the reduction of MEF2D transcriptional activity by DYRK1A. Our results indicated that DYRK1A might be a regulator of MEF2D transcriptional activity and indirectly get involved in regulation of MEF2D target genes.
Aimin Liu,Buxin Zhang,Wei Zhao,Yuanhui Tu,Qingxing Wang,Jing Li
Psoriasis is a chronic inflammatory disease characterized by abnormal hyperproliferation and differentiation. The object of this study is to explore the role of microRNA-215-5p in psoriasis-like inflammation. The expression of miR-215-5p was found to be down-regulated in pro-inflammatory factor-stimulated HaCaT cells and imiquimod (IMQ)-treated skin tissues. Overexpression of miR-215-5p suppressed the proliferation and cell cycle progression of HaCaT cells. Further, miR-215-5p agomir alleviated the disease severity, pathological features and Ki67 positive cells in IMQ-treated mice. Luciferase assay confirmed that miR-215-5p could bind to the 3′UTR of DYRK1A. The in vitro and in vivo results showed that miR-215-5p negatively regulates DYRK1A, which further inhibited EGFR and its downstream signalling pathways, AKT and ERK. Collectively, our results provide evidence that overexpression of miR-215-5p inhibits the proliferation of HaCaT cells and alleviates psoriasis-like inflammation partly by DYRK1A mediated inhibition of the EGFR signalling pathway. miR-215-5p may serve as a novel small molecule for therapeutic intervention in psoriasis.
Li Guan,Aiyun Li,Pengfei Song,Wanzhen Su,Shengjie Zhang,Jiaxin Chen,Xiangying Jiao,Weize Li
Dual-specificity tyrosine phosphorylation-regulated kinase A (DYRK1A) is a potential drug target for diabetes. The DYRK1A inhibitor can promote β cells proliferation, increase insulin secretion and reduce blood sugar in diabetes. In this paper, a series β-carboline-cinnamic acid skeletal derivatives were designed, synthesized and evaluated to inhibit the activity of DYRK1A and promote pancreatic islet β cell proliferation. Pharmacological activity showed that all of the compounds could effectively promote pancreatic islet β cell proliferation at a concentration of 1 μM, and the cell viability of compound A1, A4 and B4 reached to 381.5 %, 380.2 % and 378.5 %, respectively. Compound A1, A4 and B4 could also inhibit the expression of DYRK1A better than positive drug harmine. Further mechanistic studies showed that compound A1, A4 and B4 could inhibit DYRK1A protein expression via promoting its degradation and thus enhancing the expression of proliferative proteins PCNA and Ki67. Molecular docking showed that β-carboline scaffold of these three compounds was fully inserted into the ATP binding site and formed hydrophobic interactions with the active pocket. Besides, these three compounds were predicted to possess better drug-likeness properties using SwissADME. In conclusion, compounds A1, A4 and B4 were potent pancreatic β cell proliferative agents as DYRK1A inhibitors and might serve as promising candidates for the treatment of diabetes.
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