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Conference Paper: Prickle-1 promotes the degradation of Dishevelled by ubiquitination in liver cancer

TitlePrickle-1 promotes the degradation of Dishevelled by ubiquitination in liver cancer
Authors
Issue Date2006
PublisherAmerican Association for Cancer Research
Citation
The 97th AACR Annual Meeting, Washington, D.C., 1-5 April 2006. In Cancer Research, 2006, v. 66 n. 8S, p. 780 Abstract no. 3320 How to Cite?
AbstractAberrant activation of Wnt signaling with accumulation of β-catenin has been linked to tumorigenesis, particularly in colorectal and liver cancers. Mutations of β-catenin, adenomatous polyposis coli and axins are important factors leading to β-catenin activation but they are not frequent enough to be accountable for the accumulation of β-catenin in human hepatocellular carcinoma (HCC). In this study, we characterized the roles of Prickle-1, a Dishevelled (Dvl)-associated protein, in the regulation of Wnt/β-catenin activity in HCC. We have demonstrated that Prickle-1 interacted with Dvl3 with co-immunoprecipitation assay. In addition, Prickle-1 facilitated Dvl3 ubiquitination/degradation through its destruction box (D-box) motifs. This requirement of D-box for ubiquitination was confirmed by the use of mutant D-box 1 (R557M and L560M) and D-box 2 (R669I and L702M) generated by sequential site-directed mutagenesis. Enforced expression of Prickle-1 significantly reduced the levels of Dvl3 and β-catenin and β-catenin activity in a dose-dependent manner, and inhibited the tumorigenic properties of HCC cells in terms of colony formation and anchorage-independent growth assays. In both HCC cell lines and human HCCs, underexpression of Prickle-1 was significantly associated with overexpression of Dvl3 Prickle-1 underexpression also significantly correlated with β-catenin accumulation in cytosol and/or at membrane (P = 0.023) and tumor size (P = 0.03). Our results have defined a novel mechanistic relationship between Prickle-1 and Dvl3 in Wnt/β-catenin pathway. The enhancement of Dvl3 degradation by Prickle-1 implicates that Prickle-1 is a negative regulator of the Wnt/β-catenin signaling pathway. Our results suggest that Prickle-1 is a putative tumor suppressor in HCC. (This work was supported in part by a University Research Committee of the University of Hong Kong)
Persistent Identifierhttp://hdl.handle.net/10722/104695
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372

 

DC FieldValueLanguage
dc.contributor.authorChan, DWen_HK
dc.contributor.authorChan, PCYen_HK
dc.contributor.authorYam, JWPen_HK
dc.contributor.authorChing, YPen_HK
dc.contributor.authorNg, IOLen_HK
dc.date.accessioned2010-09-25T22:03:36Z-
dc.date.available2010-09-25T22:03:36Z-
dc.date.issued2006en_HK
dc.identifier.citationThe 97th AACR Annual Meeting, Washington, D.C., 1-5 April 2006. In Cancer Research, 2006, v. 66 n. 8S, p. 780 Abstract no. 3320-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/104695-
dc.description.abstractAberrant activation of Wnt signaling with accumulation of β-catenin has been linked to tumorigenesis, particularly in colorectal and liver cancers. Mutations of β-catenin, adenomatous polyposis coli and axins are important factors leading to β-catenin activation but they are not frequent enough to be accountable for the accumulation of β-catenin in human hepatocellular carcinoma (HCC). In this study, we characterized the roles of Prickle-1, a Dishevelled (Dvl)-associated protein, in the regulation of Wnt/β-catenin activity in HCC. We have demonstrated that Prickle-1 interacted with Dvl3 with co-immunoprecipitation assay. In addition, Prickle-1 facilitated Dvl3 ubiquitination/degradation through its destruction box (D-box) motifs. This requirement of D-box for ubiquitination was confirmed by the use of mutant D-box 1 (R557M and L560M) and D-box 2 (R669I and L702M) generated by sequential site-directed mutagenesis. Enforced expression of Prickle-1 significantly reduced the levels of Dvl3 and β-catenin and β-catenin activity in a dose-dependent manner, and inhibited the tumorigenic properties of HCC cells in terms of colony formation and anchorage-independent growth assays. In both HCC cell lines and human HCCs, underexpression of Prickle-1 was significantly associated with overexpression of Dvl3 Prickle-1 underexpression also significantly correlated with β-catenin accumulation in cytosol and/or at membrane (P = 0.023) and tumor size (P = 0.03). Our results have defined a novel mechanistic relationship between Prickle-1 and Dvl3 in Wnt/β-catenin pathway. The enhancement of Dvl3 degradation by Prickle-1 implicates that Prickle-1 is a negative regulator of the Wnt/β-catenin signaling pathway. Our results suggest that Prickle-1 is a putative tumor suppressor in HCC. (This work was supported in part by a University Research Committee of the University of Hong Kong)-
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research-
dc.relation.ispartofCancer Researchen_HK
dc.titlePrickle-1 promotes the degradation of Dishevelled by ubiquitination in liver canceren_HK
dc.typeConference_Paperen_HK
dc.identifier.emailChan, DW: dwchan@hkucc.hku.hken_HK
dc.identifier.emailChan, PCY: ahyiu@pathology.hku.hken_HK
dc.identifier.emailYam, JWP: judyyam@pathology.hku.hken_HK
dc.identifier.emailChing, YP: ypching@hkucc.hku.hken_HK
dc.identifier.emailNg, IOL: iolng@hkucc.hku.hken_HK
dc.identifier.authorityChan, DW=rp00543en_HK
dc.identifier.authorityYam, JWP=rp00468en_HK
dc.identifier.authorityChing, YP=rp00469en_HK
dc.identifier.authorityNg, IOL=rp00335en_HK
dc.identifier.hkuros120071en_HK

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