Article: Identification of XAF1 as a novel cell cycle regulator through modulating G 2/M checkpoint and interaction with checkpoint kinase 1 in gastrointestinal cancer

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TitleIdentification of XAF1 as a novel cell cycle regulator through modulating G 2/M checkpoint and interaction with checkpoint kinase 1 in gastrointestinal cancer
AuthorsWang, J1 2
Gu, Q2
Li, M2
Zhang, W1 2
Yang, M2
Zou, B2
Chan, S2
Qiao, L2
Jiang, B2
Tu, S2
Ma, J2
Hung, IF2
Lan, HY2
Wong, BCY2
Issue Date2009
PublisherOxford University Press. The Journal's web site is located at http://carcin.oxfordjournals.org/
CitationCarcinogenesis, 2009, v. 30 n. 9, p. 1507-1516 [How to Cite?]
DOI: http://dx.doi.org/10.1093/carcin/bgp155
AbstractBackground and aims: X-linked inhibitor of apoptosis-associated factor 1 (XAF1) was first recognized as an antagonist of X-linked inhibitor of apoptosis in suppressing caspase 3 activity. It has lower expression in cancer cells than normal tissue. Overexpression of XAF1 can inhibit cancer cell growth and sensitize tumor necrosis factor-related apoptosis-inducing ligand- or etoposide-induced apoptosis. The aim of this study is to elucidate the mechanism of XAF1 in regulating cell growth. Methods: Stable transfectants of gastrointestinal (GI) cancer cell lines AGS and SW1116 expressing XAF1 and vector control were generated. Cell growth, apoptosis, mitotic status and cell cycle distribution were assessed. The interaction between XAF1 and G 2/M checkpoint proteins was evaluated by immunoblotting, kinase assay and co-immunoprecipitation assay. Mitotic catastrophe was identified by occurrence of aberrant nuclei and centrosomal amplification. Results: Our results showed that overexpression of XAF1 suppressed serum-dependent cancer cell growth, induced mitotic catastrophe and G 2/M cell cycle arrest. Interestingly, XAF1 was predominantly expressed in G 2/M phase after cell cycle synchronization. XAF1 interacted with and activated checkpoint kinase 1 (Chk1), inactivated Cdc25C and lead to inactivation of Cdc2-cyclin B complex. Suppression of Chk1 abrogated XAF1-induced G 2/M arrest. Conclusions: Our findings implicate XAF1 as a novel cell cycle modulator that is recruited in G 2/M phase and thus unravel a novel function pathway of XAF1, suggesting the potential role of XAF1 as the target for the management of GI cancers. © The Author 2009. Published by Oxford University Press. All rights reserved.
ISSN0143-3334
2011 Impact Factor: 5.702
2011 SCImago Journal Rankings: 0.692
DOIhttp://dx.doi.org/10.1093/carcin/bgp155
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorWang, J
dc.contributor.authorGu, Q
dc.contributor.authorLi, M
dc.contributor.authorZhang, W
dc.contributor.authorYang, M
dc.contributor.authorZou, B
dc.contributor.authorChan, S
dc.contributor.authorQiao, L
dc.contributor.authorJiang, B
dc.contributor.authorTu, S
dc.contributor.authorMa, J
dc.contributor.authorHung, IF
dc.contributor.authorLan, HY
dc.contributor.authorWong, BCY
dc.date.accessioned2012-09-05T05:29:30Z
dc.date.available2012-09-05T05:29:30Z
dc.date.issued2009
dc.description.abstractBackground and aims: X-linked inhibitor of apoptosis-associated factor 1 (XAF1) was first recognized as an antagonist of X-linked inhibitor of apoptosis in suppressing caspase 3 activity. It has lower expression in cancer cells than normal tissue. Overexpression of XAF1 can inhibit cancer cell growth and sensitize tumor necrosis factor-related apoptosis-inducing ligand- or etoposide-induced apoptosis. The aim of this study is to elucidate the mechanism of XAF1 in regulating cell growth. Methods: Stable transfectants of gastrointestinal (GI) cancer cell lines AGS and SW1116 expressing XAF1 and vector control were generated. Cell growth, apoptosis, mitotic status and cell cycle distribution were assessed. The interaction between XAF1 and G 2/M checkpoint proteins was evaluated by immunoblotting, kinase assay and co-immunoprecipitation assay. Mitotic catastrophe was identified by occurrence of aberrant nuclei and centrosomal amplification. Results: Our results showed that overexpression of XAF1 suppressed serum-dependent cancer cell growth, induced mitotic catastrophe and G 2/M cell cycle arrest. Interestingly, XAF1 was predominantly expressed in G 2/M phase after cell cycle synchronization. XAF1 interacted with and activated checkpoint kinase 1 (Chk1), inactivated Cdc25C and lead to inactivation of Cdc2-cyclin B complex. Suppression of Chk1 abrogated XAF1-induced G 2/M arrest. Conclusions: Our findings implicate XAF1 as a novel cell cycle modulator that is recruited in G 2/M phase and thus unravel a novel function pathway of XAF1, suggesting the potential role of XAF1 as the target for the management of GI cancers. © The Author 2009. Published by Oxford University Press. All rights reserved.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationCarcinogenesis, 2009, v. 30 n. 9, p. 1507-1516 [How to Cite?]
DOI: http://dx.doi.org/10.1093/carcin/bgp155
dc.identifier.doihttp://dx.doi.org/10.1093/carcin/bgp155
dc.identifier.epage1516
dc.identifier.issn0143-3334
2011 Impact Factor: 5.702
2011 SCImago Journal Rankings: 0.692
dc.identifier.issue9
dc.identifier.scopuseid_2-s2.0-70249108452
dc.identifier.spage1507
dc.identifier.urihttp://hdl.handle.net/10722/163273
dc.identifier.volume30
dc.languageeng
dc.publisherOxford University Press. The Journal's web site is located at http://carcin.oxfordjournals.org/
dc.publisher.placeUnited Kingdom
dc.relation.ispartofCarcinogenesis
dc.relation.referencesReferences in Scopus
dc.titleIdentification of XAF1 as a novel cell cycle regulator through modulating G 2/M checkpoint and interaction with checkpoint kinase 1 in gastrointestinal cancer
dc.typeArticle
Author Affiliations
  1. Southern Medical University
  2. The University of Hong Kong