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

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.
Mesh Terms:
Animals, Autoantigens, Carcinogenesis, Carcinogens, Cell Line, Cell Proliferation, Cyclin D1, Gene Knockdown Techniques, Glycogen Synthase Kinase 3, Humans, Keratinocytes, Mice, Mice, Knockout, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-myc, Skin Neoplasms, Tetradecanoylphorbol Acetate, Transcription Factor AP-1, Wnt Signaling Pathway, p38 Mitogen-Activated Protein Kinases
Nat Commun
Date: Apr. 25, 2015
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