Cargando…

SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IκB-α/NF-κB

Sensitive to apoptosis gene (SAG)/regulator of cullins-2–Skp1-cullin–F-box protein (SCF) E3 ubiquitin ligase regulates cellular functions through ubiquitination and degradation of protein substrates. We report that, when expressed in mouse epidermis driven by the K14 promoter, SAG inhibited TPA-indu...

Descripción completa

Detalles Bibliográficos
Autores principales: Gu, Qingyang, Bowden, G. Tim, Normolle, Daniel, Sun, Yi
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064624/
https://www.ncbi.nlm.nih.gov/pubmed/17846172
http://dx.doi.org/10.1083/jcb.200612067
_version_ 1782137580904513536
author Gu, Qingyang
Bowden, G. Tim
Normolle, Daniel
Sun, Yi
author_facet Gu, Qingyang
Bowden, G. Tim
Normolle, Daniel
Sun, Yi
author_sort Gu, Qingyang
collection PubMed
description Sensitive to apoptosis gene (SAG)/regulator of cullins-2–Skp1-cullin–F-box protein (SCF) E3 ubiquitin ligase regulates cellular functions through ubiquitination and degradation of protein substrates. We report that, when expressed in mouse epidermis driven by the K14 promoter, SAG inhibited TPA-induced c-Jun levels and activator protein-1 (AP-1) activity in both in vitro primary culture, in vivo transgenic mice, and an AP-1– luciferase reporter mouse model. After AP-1 inactivation, epidermal proliferation induced by 7,12-dimethylbenz(a)-anthracene/12-O-tetradecanoylphorbol-13-acetate at the early stage of carcinogenesis was substantially inhibited. Later stage tumor formation was also substantially inhibited with prolonged latency and reduced frequency of tumor formation. Interestingly, SAG expression increased tumor size, not because of accelerated proliferation, but caused by reduced apoptosis resulting, at least in part, from nuclear factor κB (NF-κB) activation. Thus, SAG, in a manner depending on the availability of F-box proteins, demonstrated early-stage suppression of tumor formation by promoting c-Jun degradation, thereby inhibiting AP-1, and later-stage enhancement of tumor growth, by promoting inhibitor of κBα degradation to activate NF-κB and inhibit apoptosis.
format Text
id pubmed-2064624
institution National Center for Biotechnology Information
language English
publishDate 2007
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-20646242008-03-10 SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IκB-α/NF-κB Gu, Qingyang Bowden, G. Tim Normolle, Daniel Sun, Yi J Cell Biol Research Articles Sensitive to apoptosis gene (SAG)/regulator of cullins-2–Skp1-cullin–F-box protein (SCF) E3 ubiquitin ligase regulates cellular functions through ubiquitination and degradation of protein substrates. We report that, when expressed in mouse epidermis driven by the K14 promoter, SAG inhibited TPA-induced c-Jun levels and activator protein-1 (AP-1) activity in both in vitro primary culture, in vivo transgenic mice, and an AP-1– luciferase reporter mouse model. After AP-1 inactivation, epidermal proliferation induced by 7,12-dimethylbenz(a)-anthracene/12-O-tetradecanoylphorbol-13-acetate at the early stage of carcinogenesis was substantially inhibited. Later stage tumor formation was also substantially inhibited with prolonged latency and reduced frequency of tumor formation. Interestingly, SAG expression increased tumor size, not because of accelerated proliferation, but caused by reduced apoptosis resulting, at least in part, from nuclear factor κB (NF-κB) activation. Thus, SAG, in a manner depending on the availability of F-box proteins, demonstrated early-stage suppression of tumor formation by promoting c-Jun degradation, thereby inhibiting AP-1, and later-stage enhancement of tumor growth, by promoting inhibitor of κBα degradation to activate NF-κB and inhibit apoptosis. The Rockefeller University Press 2007-09-10 /pmc/articles/PMC2064624/ /pubmed/17846172 http://dx.doi.org/10.1083/jcb.200612067 Text en Copyright © 2007, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Gu, Qingyang
Bowden, G. Tim
Normolle, Daniel
Sun, Yi
SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IκB-α/NF-κB
title SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IκB-α/NF-κB
title_full SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IκB-α/NF-κB
title_fullStr SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IκB-α/NF-κB
title_full_unstemmed SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IκB-α/NF-κB
title_short SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IκB-α/NF-κB
title_sort sag/roc2 e3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-jun/ap1 and iκb-α/nf-κb
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064624/
https://www.ncbi.nlm.nih.gov/pubmed/17846172
http://dx.doi.org/10.1083/jcb.200612067
work_keys_str_mv AT guqingyang sagroc2e3ligaseregulatesskincarcinogenesisbystagedependenttargetingofcjunap1andikbanfkb
AT bowdengtim sagroc2e3ligaseregulatesskincarcinogenesisbystagedependenttargetingofcjunap1andikbanfkb
AT normolledaniel sagroc2e3ligaseregulatesskincarcinogenesisbystagedependenttargetingofcjunap1andikbanfkb
AT sunyi sagroc2e3ligaseregulatesskincarcinogenesisbystagedependenttargetingofcjunap1andikbanfkb