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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 Annual Meeting of the American Association for Cancer Research (AACR 2006), Washington, DC., 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 Annual Meeting of the American Association for Cancer Research (AACR 2006), Washington, DC., 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
dc.identifier.volume66-
dc.identifier.issue8 suppl.-
dc.identifier.spage780, abstract no. 3320-
dc.identifier.epage780, abstract no. 3320-

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