| First Author | Li L | Year | 2015 |
| Journal | Nat Commun | Volume | 6 |
| Pages | 6875 | PubMed ID | 25908095 |
| Mgi Jnum | J:222800 | Mgi Id | MGI:5645615 |
| Doi | 10.1038/ncomms7875 | Citation | Li L, et al. (2015) REGgamma is critical for skin carcinogenesis by modulating the Wnt/beta-catenin pathway. Nat Commun 6:6875 |
| abstractText | Here we report that mice deficient for the proteasome activator, REGgamma, 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 REGgamma in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGgamma elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGgamma promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGgamma activates Wnt/beta-catenin signalling by degrading GSK-3beta in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of beta-catenin. Conversely, MAPK/p38 inactivation or REGgamma deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGgamma acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/beta-catenin pathway. |
