title: REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway.
abstract: Here we report that mice deficient for the proteasome activator, REGγ, exhibit a marked resistance to TPA (12-O-tetradecanoyl-phorbol-13-acetate)-induced keratinocyte proliferation, epidermal hyperplasia and onset of papillomas compared with wild-type counterparts. Interestingly, a massive increase of REGγ in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGγ elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGγ promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGγ activates Wnt/β-catenin signalling by degrading GSK-3β in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of β-catenin. Conversely, MAPK/p38 inactivation or REGγ deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGγ acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/β-catenin pathway.
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.|Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Dang
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors.forename: Jishen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors.forename: Wangjun
authors.initials: W
authors.lastname: Yan
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Wanli
authors.initials: W
authors.lastname: Zhai
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Tong
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Gao
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Ali
authors.initials: A
authors.lastname: Amjad
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ji
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Jing
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Kaixuan
authors.initials: K
authors.lastname: Shi
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Liangfang
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors.forename: Dianwen
authors.initials: D
authors.lastname: Song
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors.forename: Tielong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors.forename: Xinghai
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors.forename: Xiaopan
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors.forename: Jin
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Molecular Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas 77030, USA.
authors.forename: Tenghui
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Molecular Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Robb E
authors.initials: RE
authors.lastname: Moses
authors.affiliation: Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Luzhou Medical College, Luzhou 646000, China.
authors.forename: Junjiang
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors.forename: Jianru
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Molecular Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D019938:Cyclin D1 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D060449:Wnt Signaling Pathway; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D001324:Autoantigens; D002273:Carcinogens; C530105:Ccnd1 protein, mouse; C099558:Ki antigen; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D018808:Transcription Factor AP-1; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; D013755:Tetradecanoylphorbol Acetate