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Nat Commun. 2015 Apr 24;6:6875. doi: 10.1038/ncomms7875.

REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway.

Author information

1
1] Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China [2] Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
2
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
3
Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
4
Department of Molecular Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
5
Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas 77030, USA.
6
Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Luzhou Medical College, Luzhou 646000, China.

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.

PMID:
25908095
DOI:
10.1038/ncomms7875
[Indexed for MEDLINE]

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