REGg is critical for skin carcinogenesis by modulating the Wnt/b-catenin pathway

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