Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes
DC Field | Value | Language |
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dc.contributor.author | Yoon, Jeong-Hwan | - |
dc.contributor.author | Jung, Su Myung | - |
dc.contributor.author | Park, Seok Hee | - |
dc.contributor.author | Kato, Mitsuyasu | - |
dc.contributor.author | Yamashita, Tadashi | - |
dc.contributor.author | Lee, In-Kyu | - |
dc.contributor.author | Sudo, Katsuko | - |
dc.contributor.author | Nakae, Susumu | - |
dc.contributor.author | Han, Jin Soo | - |
dc.contributor.author | Kim, Ok-Hee | - |
dc.contributor.author | Oh, Byung-Chul | - |
dc.contributor.author | Sumida, Takayuki | - |
dc.contributor.author | Kuroda, Masahiko | - |
dc.contributor.author | Ju, Ji-Hyeon | - |
dc.contributor.author | Jung, Kyeong Cheon | - |
dc.contributor.author | Park, Seong Hoe | - |
dc.contributor.author | Kim, Dae-Kee | - |
dc.contributor.author | Mamura, Mizuko | - |
dc.date.available | 2020-02-28T22:43:26Z | - |
dc.date.created | 2020-02-06 | - |
dc.date.issued | 2013-11 | - |
dc.identifier.issn | 1757-4676 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/14143 | - |
dc.description.abstract | Varieties of transforming growth factor- (TGF-) antagonists have been developed to intervene with excessive TGF- signalling activity in cancer. Activin receptor-like kinase5 (ALK5) inhibitors antagonize TGF- signalling by blocking TGF- receptor-activated Smad (R-Smad) phosphorylation. Here we report the novel mechanisms how ALK5 inhibitors exert a therapeutic effect on a mouse B16 melanoma model. Oral treatment with a novel ALK5 inhibitor, EW-7197 (2.5mg/kg daily) or a representative ALK5 inhibitor, LY-2157299 (75mg/kg bid) suppressed the progression of melanoma with enhanced cytotoxic T-lymphocyte (CTL) responses. Notably, ALK5 inhibitors not only blocked R-Smad phosphorylation, but also induced ubiquitin-mediated degradation of the common Smad, Smad4 mainly in CD8(+) T cells in melanoma-bearing mice. Accordingly, T-cell-specific deletion of Smad4 was sufficient to suppress the progression of melanoma. We further identified eomesodermin (Eomes), the T-box transcription factor regulating CTL functions, as a specific target repressed by TGF- via Smad4 and Smad3 in CD8(+) T cells. Thus, ALK5 inhibition enhances anti-melanoma CTL responses through ubiquitin-mediated degradation of Smad4 in addition to the direct inhibitory effect on R-Smad phosphorylation. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | WILEY | - |
dc.relation.isPartOf | EMBO MOLECULAR MEDICINE | - |
dc.subject | GROWTH-FACTOR-BETA | - |
dc.subject | TGF-BETA | - |
dc.subject | TRANSCRIPTIONAL REGULATION | - |
dc.subject | SIGNALING PATHWAY | - |
dc.subject | IMMUNE CELLS | - |
dc.subject | METASTASIS | - |
dc.subject | GENERATION | - |
dc.subject | PROTEINS | - |
dc.subject | EFFECTOR | - |
dc.subject | RESPONSIVENESS | - |
dc.title | Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes | - |
dc.type | Article | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.identifier.wosid | 000326463300007 | - |
dc.identifier.doi | 10.1002/emmm.201302524 | - |
dc.identifier.bibliographicCitation | EMBO MOLECULAR MEDICINE, v.5, no.11, pp.1720 - 1739 | - |
dc.identifier.scopusid | 2-s2.0-84887041662 | - |
dc.citation.endPage | 1739 | - |
dc.citation.startPage | 1720 | - |
dc.citation.title | EMBO MOLECULAR MEDICINE | - |
dc.citation.volume | 5 | - |
dc.citation.number | 11 | - |
dc.contributor.affiliatedAuthor | Kim, Ok-Hee | - |
dc.contributor.affiliatedAuthor | Oh, Byung-Chul | - |
dc.type.docType | Article | - |
dc.subject.keywordAuthor | ALK5 inhibitor | - |
dc.subject.keywordAuthor | Eomes | - |
dc.subject.keywordAuthor | melanoma | - |
dc.subject.keywordAuthor | Smad4 | - |
dc.subject.keywordAuthor | TGF- | - |
dc.subject.keywordPlus | GROWTH-FACTOR-BETA | - |
dc.subject.keywordPlus | TGF-BETA | - |
dc.subject.keywordPlus | TRANSCRIPTIONAL REGULATION | - |
dc.subject.keywordPlus | SIGNALING PATHWAY | - |
dc.subject.keywordPlus | IMMUNE CELLS | - |
dc.subject.keywordPlus | METASTASIS | - |
dc.subject.keywordPlus | GENERATION | - |
dc.subject.keywordPlus | PROTEINS | - |
dc.subject.keywordPlus | EFFECTOR | - |
dc.subject.keywordPlus | RESPONSIVENESS | - |
dc.relation.journalResearchArea | Research & Experimental Medicine | - |
dc.relation.journalWebOfScienceCategory | Medicine, Research & Experimental | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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