title: Identification of Cyclin-Dependent Kinase 1 as a Novel Regulator of Type I Interferon Signaling in Systemic Lupus Erythematosus.
abstract: Type I interferon (IFN) signaling is regarded as a central pathogenic pathway in systemic lupus erythematosus (SLE). Specific inhibition of this pathway is a core area for the development of new therapies for SLE. This study was undertaken to clarify the pathogenic mechanism involved and to identify new therapeutic targets, using a high-throughput screening platform to determine novel regulators that contribute to the overactivation of the type I IFN signaling pathway in SLE.
  
  
  
  A high-throughput IFN-stimulated response element (ISRE)-luciferase assay was used to screen for candidate genes that regulate the IFN signaling pathway. Western blotting was used to confirm the regulatory function of CDK1. SYBR Green quantitative reverse transcriptase-polymerase chain reaction was used to detect the expression of individual IFN-stimulated genes (ISGs). The differential expression of CDK1 and ISGs in SLE patients and healthy controls was analyzed using RNA sequencing data and a microarray.
  
  
  
  The high-throughput ISRE-luciferase assay revealed that CDK1 enhanced type I IFN signaling. Consistent with this finding, CDK1 promoted the type I IFN-induced phosphorylation of STAT-1 and the up-regulated expression of ISGs. CDK1 expression was elevated in peripheral blood mononuclear cells (PBMCs) and kidney biopsy specimens from SLE patients and correlated positively with their IFN scores. A CDK1 inhibitor reduced the expression of ISGs in PBMCs from SLE patients and in renal cells from mice with lupus.
  
  
  
  Our findings indicate that CDK1 is a positive regulator of the IFN signaling pathway. The overexpression of CDK1 might contribute to the abnormally amplified type I IFN signaling in SLE, and the inhibition of CDK1 could be used to down-regulate type I IFN signaling in SLE.
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Wu
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Xia
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Dai
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Shanghai Jiao Tong University School of Medicine, and Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jianyang
authors.initials: J
authors.lastname: Ma
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Shanghai Jiao Tong University School of Medicine, and Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yuanjia
authors.initials: Y
authors.lastname: Tang
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
authors.affiliation: Yihong Yao, PhD: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, and MedImmune, Gaithersburg, Maryland.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Qu
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Shanghai Jiao Tong University School of Medicine and Chinese Academy of Sciences, Shanghai, China; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Collaborative Innovation Center for Translational Medicine at Shanghai Jiao Tong University School of Medicine; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D016203:CDC2 Protein Kinase; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000187:drug effects / Q000276:immunology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008181:Lupus Nephritis / Q000378:metabolism*; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation; D011804:Quinolines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013844:Thiazoles / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D007370:Interferon Type I; D011804:Quinolines; C512984:RO 3306; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D013844:Thiazoles; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases