title: Dux4 induces cell cycle arrest at G1 phase through upregulation of p21 expression.
abstract: It has been implicated that Dux4 plays crucial roles in development of facioscapulohumeral dystrophy. But the underlying myopathic mechanisms and related down-stream events of this retrogene were far from clear. Here, we reported that overexpression of Dux4 in a cell model TE671 reduced cell proliferation rate, and increased G1 phase accumulation. We also determined the impact of Dux4 on p53/p21 signal pathway, which controls the checkpoint in cell cycle progression. Overexpression of Dux4 increased p21 mRNA and protein level, while expression of p53, phospho-p53 remained unchanged. Silencing p21 rescued Dux4 mediated proliferation defect and cell cycle arrest. Furthermore, we demonstrated that enhanced Dux4 expression increased p21 promoter activity and elevated expression of Sp1 transcription factor. Mutation of Sp1 binding site decreased dux4 induced p21 promoter activation. Chromatin immunoprecipitation (ChIP) assays confirmed the Dux4-induced binding of Sp1 to p21 promoter in vivo. These results suggest that Dux4 might induce proliferation inhibition and G1 phase arrest through upregulation of p21.
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing 100034, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing 100034, China.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing 100034, China.
authors.forename: Suqin
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing 100034, China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Hao
authors.affiliation: The Institute of Cardiovascular Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Health Ministry, Beijing 100191, China.
authors.forename: Lemin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: The Department of Cardiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Boda
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing 100034, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing 100034, China.
authors.forename: He
authors.initials: H
authors.lastname: Lv
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing 100034, China. Electronic address: yuanyun2002@sohu.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yuan
mesh_terms: D001665:Binding Sites / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000209:etiology / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Cell cycle; Dux4; FSHD; p21