SMAD4 Suppresses AURKA-Induced Metastatic Phenotypes via Degradation of AURKA in a TGF?-Independent Manner

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dc.contributor.authorJia, Lina
dc.contributor.authorLee, Hun Seok
dc.contributor.authorWu, Chun Fu
dc.contributor.authorKundu, Juthika
dc.contributor.authorPark, Sang Gyu
dc.contributor.authorKim, Ryong Nam
dc.contributor.authorWang, Li-Hui
dc.date.accessioned2025-01-06T17:44:54Z
dc.date.available2025-01-06T17:44:54Z
dc.date.issued2014
dc.description.abstractSMAD4 has been suggested to inhibit the activity of the WNT/beta-catenin signaling pathway in cancer. However, the mechanism by which SMAD4 antagonizes WNT/b-catenin signaling in cancer remains largely unknown. Aurora A kinase (AURKA), which is frequently overexpressed in cancer, increases the transcriptional activity of beta-catenin/T-cell factor (TCF) complex by stabilizing beta-catenin through the inhibition of GSK-3 beta. Here, SMAD4 modulated AURKA in a TGF beta-independent manner. Overexpression of SMAD4 significantly suppressed AURKA function, including colony formation, migration, and invasion of cell lines. In addition, SMAD4 bound to AURKA induced degradation of AURKA by the proteasome. A luciferase activity assay revealed that the transcriptional activity of the beta-catenin/TCF complex was elevated by AURKA, but decreased by SMAD4 overexpression. Moreover, target gene analysis showed that SMAD4 abrogated the AURKA-mediated increase of beta-catenin target genes. However, this inhibitory effect of SMAD4 was abolished by overexpression of AURKA or silencing of AURKA in SMAD4-overexpressed cells. Meanwhile, the SMAD4-mediated repression of AURKA and beta-catenin was independent of TGF beta signaling because blockage of TGF beta R1 or restoration of TGF beta signaling did not prevent suppression of AURKA and beta-catenin signaling by SMAD4. These results indicate that the tumor-suppressive function of SMAD4 is mediated by down regulation of b-catenin transcriptional activity via AURKA degradation in a TGF beta-independent manner. (C)2014 AACR.
dc.description.sponsorshipR&D Program for Society of the National Research Foundation (NRF) - Ministry of Science, ICT & Future Planning [NRF-2013M3C8A1078433]; Global Core Research Center (GCRC) from the National Research Foundation (NRF) [2012-0001194]; Ministry of Education, Science and Technology (MEST), Republic of Korea
dc.description.sponsorshipThis research was supported by the R&D Program for Society of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (Grant number: NRF-2013M3C8A1078433) and by the Global Core Research Center (GCRC) grant (Grant number: 2012-0001194) from the National Research Foundation (NRF), Ministry of Education, Science and Technology (MEST), Republic of Korea.
dc.identifier.doi10.1158/1541-7786.MCR-14-0191
dc.identifier.endpage1795
dc.identifier.issn1541-7786
dc.identifier.issn1557-3125
dc.identifier.issue12
dc.identifier.pmid25061104
dc.identifier.scopus2-s2.0-84919331297
dc.identifier.scopusqualityQ1
dc.identifier.startpage1779
dc.identifier.urihttps://doi.org/10.1158/1541-7786.MCR-14-0191
dc.identifier.urihttps://hdl.handle.net/20.500.14669/3237
dc.identifier.volume12
dc.identifier.wosWOS:000346560400008
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherAmer Assoc Cancer Research
dc.relation.ispartofMolecular Cancer Research
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_20241211
dc.subjectColon-Carcınoma Cells
dc.subjectBımolecular Fluorescence Complementatıon
dc.subjectGrowth-Factor-Beta
dc.subjectAurora-A
dc.subjectCancer-Cells
dc.subjectCentrosome Amplıfıcatıon
dc.subjectPancreatıc-Cancer
dc.subjectSıgnalıng Pathway
dc.subjectTumor Suppressıon
dc.subjectOvarıan-Cancer
dc.titleSMAD4 Suppresses AURKA-Induced Metastatic Phenotypes via Degradation of AURKA in a TGF?-Independent Manner
dc.typeArticle

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