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; Wei Xu; Quan Huang; Jin He; Jian Liu; Tenghui Chen; Robb E. Moses; Junjiang Fu; Jianru Xiao; Xiaotao Li

doi:10.1038/ncomms7875

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 journal › Article › peer-review

51 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 language	English (US)
Article number	6875
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7875
State	Published - Apr 24 2015
Externally published	Yes

ASJC Scopus subject areas

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

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10.1038/ncomms7875

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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, Cai, X, Xu, W, Huang, Q, He, J, Liu, J, Chen, T, Moses, RE, 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

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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 Moses, {Robb E.} and Junjiang Fu and Jianru Xiao and Xiaotao Li",

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doi = "10.1038/ncomms7875",

language = "English (US)",

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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 E.

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.

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ER -

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

Abstract

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