REGγ 3 is critical for skin carcinogenesis by modulating the Wnt/β 2-catenin pathway

Here we report that mice deficient for the proteasome activator, REGγ 3, 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 3 in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGγ 3 elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGγ 3 promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGγ 3 activates Wnt/β 2-catenin signalling by degrading GSK-3β 2 in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of β 2-catenin. Conversely, MAPK/p38 inactivation or REGγ 3 deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGγ 3 acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/β 2-catenin pathway.