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

Lei Li, Yongyan Dang, Jishen Zhang, Wangjun Yan, Wanli Zhai, Hui Chen, Ke Li, Lu Tong, Xiao Gao, Ali Amjad, Lei Ji, Tiantian Jing, Ziwei Jiang, Kaixuan Shi, Liangfang Yao, Dianwen Song, Tielong Liu, Xinghai Yang, Cheng Yang, Xiaopan CaiWei Xu, Quan Huang, Jin He, Jian Liu, Tenghui Chen, Robb E. Moses, Junjiang Fu, Jianru Xiao, Xiaotao Li

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number6875
JournalNature communications
Volume6
DOIs
StatePublished - Apr 24 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Li, L., Dang, Y., Zhang, J., Yan, W., Zhai, W., Chen, H., Li, K., Tong, L., Gao, X., Amjad, A., Ji, L., Jing, T., Jiang, Z., Shi, K., Yao, L., Song, D., Liu, T., Yang, X., Yang, C., ... Li, X. (2015). REGγ 3 is critical for skin carcinogenesis by modulating the Wnt/β 2-catenin pathway. Nature communications, 6, [6875]. https://doi.org/10.1038/ncomms7875