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Article: Zic2 synergistically enhances Hedgehog signalling through nuclear retention of Gli1 in cervical cancer cells

TitleZic2 synergistically enhances Hedgehog signalling through nuclear retention of Gli1 in cervical cancer cells
Authors
Keywordscervical cancer
Gli1
Hedgehog
tumourigenicity
Zic2
Issue Date2011
PublisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
Citation
Journal Of Pathology, 2011, v. 225 n. 4, p. 525-534 How to Cite?
AbstractAberrant activation of Hedgehog (Hh) signalling has been implicated in the pathogenesis of human cancers. However, the cognate molecular mechanisms contributing to this disregulated pathway are incompletely understood. In this study, we showed that Zic2 was frequently over-expressed and associated with high-grade cervical cancer (p = 0.032), high levels of Gli1 (p < 0.001) and CyclinD1 (p < 0.001) by immunohistochemical and quantitative RT-PCR analyses. Further biochemical studies using luciferase reporter, co-immunoprecipitation, subcellular fractionation and immunofluorescence analyses demonstrated that Zic2 can physically interact with Gli1 and retain it in the nucleus, which in turn increases Gli-mediated transcriptional activity. Gain- and loss-of-function analyses of Zic2 showed that Zic2 could increase Hh signalling activity, cell proliferation and anchorage-independent growth ability in cervical cancer cells. Conversely, deletion of the zinc finger domain at C-terminus of Zic2 significantly abrogated its interaction with Gli1, the retention of Gli1 in the nucleus, effects on Hh signalling activity and oncogenic properties in cervical cancer cells. Our findings suggest that Zic2 is a positive modulator increasing Gli1 transcriptional and oncogenic activity by retaining Gli1 in the nucleus of cervical cancer cells. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Persistent Identifierhttp://hdl.handle.net/10722/135676
ISSN
2015 Impact Factor: 7.381
2015 SCImago Journal Rankings: 4.176
ISI Accession Number ID
Funding AgencyGrant Number
Wong Check She Charitable Foundation
Funding Information:

We thank Professor J Aruga, Riken Brain Science Institute, Wako-shi, Saitama, Japan, for providing HA-tagged-Zic2 expressing construct; Professor CC Hui, Hospital for Sick Children, Toronto, Canada, for providing the Gli1-expressing construct (Gli1/pCMV) and the P8XGli-luc reporter plasmid; and Mr Philos CT Yip for technical assistance. This study was supported by the Wong Check She Charitable Foundation.

References

 

DC FieldValueLanguage
dc.contributor.authorChan, DWen_HK
dc.contributor.authorLiu, VWSen_HK
dc.contributor.authorLeung, LYen_HK
dc.contributor.authorYao, KMen_HK
dc.contributor.authorChan, KKLen_HK
dc.contributor.authorCheung, ANYen_HK
dc.contributor.authorNgan, HYSen_HK
dc.date.accessioned2011-07-27T01:39:12Z-
dc.date.available2011-07-27T01:39:12Z-
dc.date.issued2011en_HK
dc.identifier.citationJournal Of Pathology, 2011, v. 225 n. 4, p. 525-534en_HK
dc.identifier.issn0022-3417en_HK
dc.identifier.urihttp://hdl.handle.net/10722/135676-
dc.description.abstractAberrant activation of Hedgehog (Hh) signalling has been implicated in the pathogenesis of human cancers. However, the cognate molecular mechanisms contributing to this disregulated pathway are incompletely understood. In this study, we showed that Zic2 was frequently over-expressed and associated with high-grade cervical cancer (p = 0.032), high levels of Gli1 (p < 0.001) and CyclinD1 (p < 0.001) by immunohistochemical and quantitative RT-PCR analyses. Further biochemical studies using luciferase reporter, co-immunoprecipitation, subcellular fractionation and immunofluorescence analyses demonstrated that Zic2 can physically interact with Gli1 and retain it in the nucleus, which in turn increases Gli-mediated transcriptional activity. Gain- and loss-of-function analyses of Zic2 showed that Zic2 could increase Hh signalling activity, cell proliferation and anchorage-independent growth ability in cervical cancer cells. Conversely, deletion of the zinc finger domain at C-terminus of Zic2 significantly abrogated its interaction with Gli1, the retention of Gli1 in the nucleus, effects on Hh signalling activity and oncogenic properties in cervical cancer cells. Our findings suggest that Zic2 is a positive modulator increasing Gli1 transcriptional and oncogenic activity by retaining Gli1 in the nucleus of cervical cancer cells. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130en_HK
dc.relation.ispartofJournal of Pathologyen_HK
dc.subjectcervical canceren_HK
dc.subjectGli1en_HK
dc.subjectHedgehogen_HK
dc.subjecttumourigenicityen_HK
dc.subjectZic2en_HK
dc.subject.meshAdenocarcinoma - genetics - metabolism - pathologyen_HK
dc.subject.meshCell Line, Transformeden_HK
dc.subject.meshCell Line, Tumoren_HK
dc.subject.meshCell Nucleus - metabolismen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshGene Expression Regulation, Neoplasticen_HK
dc.subject.meshHedgehog Proteins - genetics - metabolismen_HK
dc.subject.meshHumansen_HK
dc.subject.meshNuclear Proteins - genetics - metabolismen_HK
dc.subject.meshRNA, Messenger - metabolismen_HK
dc.subject.meshSignal Transductionen_HK
dc.subject.meshTranscription Factors - genetics - metabolismen_HK
dc.subject.meshUterine Cervical Neoplasms - genetics - metabolism - pathologyen_HK
dc.titleZic2 synergistically enhances Hedgehog signalling through nuclear retention of Gli1 in cervical cancer cellsen_HK
dc.typeArticleen_HK
dc.identifier.emailChan, DW: dwchan@hku.hken_HK
dc.identifier.emailLiu, VWS: vwsliu@hkusua.hku.hken_HK
dc.identifier.emailYao, KM: kmyao@hku.hken_HK
dc.identifier.emailChan, KKL: kklchan@hkucc.hku.hken_HK
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hken_HK
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hken_HK
dc.identifier.authorityChan, DW=rp00543en_HK
dc.identifier.authorityLiu, VWS=rp00341en_HK
dc.identifier.authorityYao, KM=rp00344en_HK
dc.identifier.authorityChan, KKL=rp00499en_HK
dc.identifier.authorityCheung, ANY=rp00542en_HK
dc.identifier.authorityNgan, HYS=rp00346en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/path.2901en_HK
dc.identifier.pmid21661123-
dc.identifier.scopuseid_2-s2.0-81355138832en_HK
dc.identifier.hkuros187274en_US
dc.identifier.hkuros204909-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-81355138832&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume225en_HK
dc.identifier.issue4en_HK
dc.identifier.spage525en_HK
dc.identifier.epage534en_HK
dc.identifier.eissn1096-9896-
dc.identifier.isiWOS:000297299500006-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridChan, DW=26533900600en_HK
dc.identifier.scopusauthoridLiu, VWS=7006405113en_HK
dc.identifier.scopusauthoridLeung, LY=54420450900en_HK
dc.identifier.scopusauthoridYao, KM=7403234578en_HK
dc.identifier.scopusauthoridChan, KKL=8655666700en_HK
dc.identifier.scopusauthoridCheung, ANY=54927484100en_HK
dc.identifier.scopusauthoridNgan, HYS=34571944100en_HK

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