title: TRAF1 Is Critical for DMBA/Solar UVR-Induced Skin Carcinogenesis.
abstract: TRAF1 is a member of the TRAF protein family, which regulates the canonical and noncanonical NF-κB signaling cascades. Although aberrant TRAF1 expression in tumors has been reported, the role of TRAF1 remains elusive. Here, we report that TRAF1 is required for solar UV-induced skin carcinogenesis. Immunohistochemical analysis showed that TRAF1 expression is up-regulated in human actinic keratosis and squamous cell carcinoma. In vivo studies indicated that TRAF1 expression levels in mouse skin are induced by short-term solar UV irradiation, and a long-term skin carcinogenesis study showed that deletion of TRAF1 in mice results in a significant inhibition of skin tumor formation. Moreover, we show that TRAF1 is required for solar UV-induced extracellular signal-regulated kinase-5 (ERK5) phosphorylation and the expression of AP-1 family members (c-Fos/c-Jun). Mechanistic studies showed that TRAF1 expression enhances the ubiquitination of ERK5 on lysine 184, which is necessary for its kinase activity and AP-1 activation. Overall, our results suggest that TRAF1 mediates ERK5 activity by regulating the upstream effectors of ERK5 and also by modulating its ubiquitination status. Targeting TRAF1 function might lead to strategies for preventing and treating skin cancer.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: Joohyun
authors.initials: J
authors.lastname: Ryu
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Min
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Oi
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Bai
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Zykova
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyogo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Moriyama
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA. Electronic address: zgdong@hi.umn.edu.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000528:radiation effects*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D000078404:Epidermal Cells; D004817:Epidermis / Q000473:pathology; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D005786:Gene Expression Regulation; D015603:Keratinocytes / Q000166:cytology / Q000473:pathology / Q000528:radiation effects*; D055623:Keratosis, Actinic / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism / Q000528:radiation effects; D011897:Random Allocation; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000209:etiology / Q000503:physiopathology; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D015854:Up-Regulation
chemical_list: D047990:TNF Receptor-Associated Factor 1; D015127:9,10-Dimethyl-1,2-benzanthracene; D048054:Mitogen-Activated Protein Kinase 7
keywords: 12-O-tetradecanoylphorbol-13-acetate; 7,12-dimethylbenz[a]anthracene; AK; DMBA; ERK; ERK kinase 5; HA; HEK; HEKa; K; MAPK; MEK5; SCC; TPA; WT; actinic keratosis; adult human epidermal keratinocyte; extracellular signal-regulated protein kinase; hemagglutinin; human embryonic kidney; keratin; mitogen-activated protein kinase; squamous cell carcinoma; wild type