A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.

Ling Wu; Xing Chen; Junjie Zhao; Bradley Martin; Jarod A Zepp; Jennifer S Ko; Chunfang Gu; Gang Cai; Wenjun Ouyang; Ganes Sen; George R Stark; Bing Su; Charlotte M Vines; Cathy Tournier; Thomas A Hamilton; Allison Vidimos; Brian Gastman; Caini Liu; Xiaoxia Li

doi:10.1084/jem.20150204

A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.

Ling Wu, Xing Chen, Junjie Zhao, Bradley Martin, Jarod A Zepp, Jennifer S Ko, Chunfang Gu, Gang Cai, Wenjun Ouyang, Ganes Sen, George R Stark, Bing Su, Charlotte M Vines, Cathy Tournier, Thomas A Hamilton, Allison Vidimos, Brian Gastman, Caini Liu, Xiaoxia Li

Research output: Contribution to journal › Article › peer-review

Abstract

Although IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. Previous studies suggest that IL-17 (IL-17A) sustains a chronic inflammatory microenvironment that favors tumor formation. Here we report a novel IL-17-mediated cascade via the IL-17R-Act1-TRAF4-MEKK3-ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation. Although this axis dictates the expression of target genes Steap4 (a metalloreductase for cell metabolism and proliferation) and p63 (a transcription factor for epidermal stem cell proliferation), Steap4 is required for the IL-17-induced sustained expansion of p63(+) basal cells in the epidermis. P63 (a positive transcription factor for the Traf4 promoter) induces TRAF4 expression in keratinocytes. Thus, IL-17-induced Steap4-p63 expression forms a positive feedback loop through p63-mediated TRAF4 expression, driving IL-17-dependent sustained activation of the TRAF4-ERK5 axis for keratinocyte proliferation and tumor formation.

Original language	English
Journal	The Journal of experimental medicine
Volume	212
Issue number	10
DOIs	https://doi.org/10.1084/jem.20150204
Publication status	Published - 21 Sept 2015

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Wu, L., Chen, X., Zhao, J., Martin, B., Zepp, J. A., Ko, J. S., Gu, C., Cai, G., Ouyang, W., Sen, G., Stark, G. R., Su, B., Vines, C. M., Tournier, C., Hamilton, T. A., Vidimos, A., Gastman, B., Liu, C., & Li, X. (2015). A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis. The Journal of experimental medicine, 212(10). https://doi.org/10.1084/jem.20150204

@article{53f63adab3d542cf8ab502bb6188ec8b,

title = "A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.",

abstract = "Although IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. Previous studies suggest that IL-17 (IL-17A) sustains a chronic inflammatory microenvironment that favors tumor formation. Here we report a novel IL-17-mediated cascade via the IL-17R-Act1-TRAF4-MEKK3-ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation. Although this axis dictates the expression of target genes Steap4 (a metalloreductase for cell metabolism and proliferation) and p63 (a transcription factor for epidermal stem cell proliferation), Steap4 is required for the IL-17-induced sustained expansion of p63(+) basal cells in the epidermis. P63 (a positive transcription factor for the Traf4 promoter) induces TRAF4 expression in keratinocytes. Thus, IL-17-induced Steap4-p63 expression forms a positive feedback loop through p63-mediated TRAF4 expression, driving IL-17-dependent sustained activation of the TRAF4-ERK5 axis for keratinocyte proliferation and tumor formation.",

author = "Ling Wu and Xing Chen and Junjie Zhao and Bradley Martin and Zepp, {Jarod A} and Ko, {Jennifer S} and Chunfang Gu and Gang Cai and Wenjun Ouyang and Ganes Sen and Stark, {George R} and Bing Su and Vines, {Charlotte M} and Cathy Tournier and Hamilton, {Thomas A} and Allison Vidimos and Brian Gastman and Caini Liu and Xiaoxia Li",

note = "T32 GM007250, NIGMS NIH HHS, United States",

year = "2015",

month = sep,

day = "21",

doi = "10.1084/jem.20150204",

language = "English",

volume = "212",

journal = "The Journal of experimental medicine",

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Wu, L, Chen, X, Zhao, J, Martin, B, Zepp, JA, Ko, JS, Gu, C, Cai, G, Ouyang, W, Sen, G, Stark, GR, Su, B, Vines, CM, Tournier, C, Hamilton, TA, Vidimos, A, Gastman, B, Liu, C & Li, X 2015, 'A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.', The Journal of experimental medicine, vol. 212, no. 10. https://doi.org/10.1084/jem.20150204

TY - JOUR

T1 - A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.

AU - Wu, Ling

AU - Chen, Xing

AU - Zhao, Junjie

AU - Martin, Bradley

AU - Zepp, Jarod A

AU - Ko, Jennifer S

AU - Gu, Chunfang

AU - Cai, Gang

AU - Ouyang, Wenjun

AU - Sen, Ganes

AU - Stark, George R

AU - Su, Bing

AU - Vines, Charlotte M

AU - Tournier, Cathy

AU - Hamilton, Thomas A

AU - Vidimos, Allison

AU - Gastman, Brian

AU - Liu, Caini

AU - Li, Xiaoxia

N1 - T32 GM007250, NIGMS NIH HHS, United States

PY - 2015/9/21

Y1 - 2015/9/21

N2 - Although IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. Previous studies suggest that IL-17 (IL-17A) sustains a chronic inflammatory microenvironment that favors tumor formation. Here we report a novel IL-17-mediated cascade via the IL-17R-Act1-TRAF4-MEKK3-ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation. Although this axis dictates the expression of target genes Steap4 (a metalloreductase for cell metabolism and proliferation) and p63 (a transcription factor for epidermal stem cell proliferation), Steap4 is required for the IL-17-induced sustained expansion of p63(+) basal cells in the epidermis. P63 (a positive transcription factor for the Traf4 promoter) induces TRAF4 expression in keratinocytes. Thus, IL-17-induced Steap4-p63 expression forms a positive feedback loop through p63-mediated TRAF4 expression, driving IL-17-dependent sustained activation of the TRAF4-ERK5 axis for keratinocyte proliferation and tumor formation.

AB - Although IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. Previous studies suggest that IL-17 (IL-17A) sustains a chronic inflammatory microenvironment that favors tumor formation. Here we report a novel IL-17-mediated cascade via the IL-17R-Act1-TRAF4-MEKK3-ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation. Although this axis dictates the expression of target genes Steap4 (a metalloreductase for cell metabolism and proliferation) and p63 (a transcription factor for epidermal stem cell proliferation), Steap4 is required for the IL-17-induced sustained expansion of p63(+) basal cells in the epidermis. P63 (a positive transcription factor for the Traf4 promoter) induces TRAF4 expression in keratinocytes. Thus, IL-17-induced Steap4-p63 expression forms a positive feedback loop through p63-mediated TRAF4 expression, driving IL-17-dependent sustained activation of the TRAF4-ERK5 axis for keratinocyte proliferation and tumor formation.

U2 - 10.1084/jem.20150204

DO - 10.1084/jem.20150204

M3 - Article

C2 - 26347473

SN - 1540-9538

VL - 212

JO - The Journal of experimental medicine

JF - The Journal of experimental medicine

IS - 10

ER -

A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.

Abstract

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