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 Cai & 9 others Wei Xu, Quan Huang, Jin He, Jian Liu, Tenghui Chen, Robb Moses, Junjiang Fu, Jianru Xiao, Xiaotao Li

Research output: Contribution to journalArticle

25 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Catenins
p38 Mitogen-Activated Protein Kinases
Tetradecanoylphorbol Acetate
acetates
Skin
Carcinogenesis
activation
Chemical activation
cells
effectors
deletion
Glycogen Synthase Kinase 3
stimulation
deactivation
Transcription Factor AP-1
Papilloma
mice
Proteasome Endopeptidase Complex
Transcription
Keratinocytes

ASJC Scopus subject areas

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

Cite this

REGγ 3 is critical for skin carcinogenesis by modulating the Wnt/β 2-catenin pathway. / Li, Lei; Dang, Yongyan; Zhang, Jishen; Yan, Wangjun; Zhai, Wanli; Chen, Hui; Li, Ke; Tong, Lu; Gao, Xiao; Amjad, Ali; Ji, Lei; Jing, Tiantian; Jiang, Ziwei; Shi, Kaixuan; Yao, Liangfang; Song, Dianwen; Liu, Tielong; Yang, Xinghai; Yang, Cheng; Cai, Xiaopan; Xu, Wei; Huang, Quan; He, Jin; Liu, Jian; Chen, Tenghui; Moses, Robb; Fu, Junjiang; Xiao, Jianru; Li, Xiaotao.

In: Nature Communications, Vol. 6, 6875, 24.04.2015.

Research output: Contribution to journalArticle

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, Cai, X, Xu, W, Huang, Q, He, J, Liu, J, Chen, T, Moses, R, Fu, J, Xiao, J & Li, X 2015, 'REGγ 3 is critical for skin carcinogenesis by modulating the Wnt/β 2-catenin pathway', Nature Communications, vol. 6, 6875. https://doi.org/10.1038/ncomms7875
Li, Lei ; Dang, Yongyan ; Zhang, Jishen ; Yan, Wangjun ; Zhai, Wanli ; Chen, Hui ; Li, Ke ; Tong, Lu ; Gao, Xiao ; Amjad, Ali ; Ji, Lei ; Jing, Tiantian ; Jiang, Ziwei ; Shi, Kaixuan ; Yao, Liangfang ; Song, Dianwen ; Liu, Tielong ; Yang, Xinghai ; Yang, Cheng ; Cai, Xiaopan ; Xu, Wei ; Huang, Quan ; He, Jin ; Liu, Jian ; Chen, Tenghui ; Moses, Robb ; Fu, Junjiang ; Xiao, Jianru ; Li, Xiaotao. / REGγ 3 is critical for skin carcinogenesis by modulating the Wnt/β 2-catenin pathway. In: Nature Communications. 2015 ; Vol. 6.
@article{6346e962c7d24a8ea83a3ae83947432c,
title = "REGγ 3 is critical for skin carcinogenesis by modulating the Wnt/β 2-catenin pathway",
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.",
author = "Lei Li and Yongyan Dang and Jishen Zhang and Wangjun Yan and Wanli Zhai and Hui Chen and Ke Li and Lu Tong and Xiao Gao and Ali Amjad and Lei Ji and Tiantian Jing and Ziwei Jiang and Kaixuan Shi and Liangfang Yao and Dianwen Song and Tielong Liu and Xinghai Yang and Cheng Yang and Xiaopan Cai and Wei Xu and Quan Huang and Jin He and Jian Liu and Tenghui Chen and Robb Moses and Junjiang Fu and Jianru Xiao and Xiaotao Li",
year = "2015",
month = "4",
day = "24",
doi = "10.1038/ncomms7875",
language = "English (US)",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - REGγ 3 is critical for skin carcinogenesis by modulating the Wnt/β 2-catenin pathway

AU - Li, Lei

AU - Dang, Yongyan

AU - Zhang, Jishen

AU - Yan, Wangjun

AU - Zhai, Wanli

AU - Chen, Hui

AU - Li, Ke

AU - Tong, Lu

AU - Gao, Xiao

AU - Amjad, Ali

AU - Ji, Lei

AU - Jing, Tiantian

AU - Jiang, Ziwei

AU - Shi, Kaixuan

AU - Yao, Liangfang

AU - Song, Dianwen

AU - Liu, Tielong

AU - Yang, Xinghai

AU - Yang, Cheng

AU - Cai, Xiaopan

AU - Xu, Wei

AU - Huang, Quan

AU - He, Jin

AU - Liu, Jian

AU - Chen, Tenghui

AU - Moses, Robb

AU - Fu, Junjiang

AU - Xiao, Jianru

AU - Li, Xiaotao

PY - 2015/4/24

Y1 - 2015/4/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84928812853&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84928812853&partnerID=8YFLogxK

U2 - 10.1038/ncomms7875

DO - 10.1038/ncomms7875

M3 - Article

VL - 6

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 6875

ER -