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Article: p53-dependent Chk1 phosphorylation is required for maintenance of prolonged G 2 arrest

Titlep53-dependent Chk1 phosphorylation is required for maintenance of prolonged G 2 arrest
Authors
Issue Date2007
Citation
Radiation Research, 2007, v. 168 n. 6, p. 706-715 How to Cite?
AbstractTargeting checkpoint kinases has been shown to have a potential chemosensitizing effect in cancer treatment. However, inhibitors of such kinases preferentially abrogate the DNA damage-induced G 2 checkpoint in p53 -/- as opposed to p53 +/+ cells. The mechanisms by which p53 (TP53) can prevent abrogation of the G 2 checkpoint are unclear. Using normal human diploid p53 +/+ and p53 -/- fibroblasts as model systems, we have compared the effects of three checkpoint inhibitors, caffeine, staurosporine and UCN-01, on γ-radiation-induced G 2 arrest. The G 2 arrest in p53 +/+ cells was abrogated by caffeine, but not by staurosporine and UCN-01, whereas the G 2 arrest in p53 -/- cells was sensitive to all three inhibitors. Chk2 (CHEK1) phosphorylation was maintained in the presence of all three inhibitors in both p53 +/+ and p53 -/- cells. Chk1 phosphorylation was maintained only in the presence of staurosporine and UCN-01 in p53 +/+ cells. In the presence of caffeine Chk1 phosphorylation was inhibited regardless of p53 status. The pathway of Chk1 phosphorylation → Cdc25A degradation → inhibition of cyclin B1/Cdk1 activity → G 2 arrest is accordingly resistant to staurosporine and UCN-01 in p53 +/+ cells. Moreover, sustained phosphorylation of Chk1 in the presence of staurosporine and UCN-01 is strongly related to phosphorylation of p53. The present study suggests the unique role of Chk1 in preventing abrogation of the G 2 checkpoint in p53 +/+ cells. © 2007 by Radiation Research Society.
Persistent Identifierhttp://hdl.handle.net/10722/172957
ISSN
2015 Impact Factor: 3.022
2015 SCImago Journal Rankings: 1.493
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorWang, XQen_US
dc.contributor.authorStanbridge, EJen_US
dc.contributor.authorLao, Xen_US
dc.contributor.authorCai, Qen_US
dc.contributor.authorFan, STen_US
dc.contributor.authorRedpath, JLen_US
dc.date.accessioned2012-10-30T06:26:01Z-
dc.date.available2012-10-30T06:26:01Z-
dc.date.issued2007en_US
dc.identifier.citationRadiation Research, 2007, v. 168 n. 6, p. 706-715en_US
dc.identifier.issn0033-7587en_US
dc.identifier.urihttp://hdl.handle.net/10722/172957-
dc.description.abstractTargeting checkpoint kinases has been shown to have a potential chemosensitizing effect in cancer treatment. However, inhibitors of such kinases preferentially abrogate the DNA damage-induced G 2 checkpoint in p53 -/- as opposed to p53 +/+ cells. The mechanisms by which p53 (TP53) can prevent abrogation of the G 2 checkpoint are unclear. Using normal human diploid p53 +/+ and p53 -/- fibroblasts as model systems, we have compared the effects of three checkpoint inhibitors, caffeine, staurosporine and UCN-01, on γ-radiation-induced G 2 arrest. The G 2 arrest in p53 +/+ cells was abrogated by caffeine, but not by staurosporine and UCN-01, whereas the G 2 arrest in p53 -/- cells was sensitive to all three inhibitors. Chk2 (CHEK1) phosphorylation was maintained in the presence of all three inhibitors in both p53 +/+ and p53 -/- cells. Chk1 phosphorylation was maintained only in the presence of staurosporine and UCN-01 in p53 +/+ cells. In the presence of caffeine Chk1 phosphorylation was inhibited regardless of p53 status. The pathway of Chk1 phosphorylation → Cdc25A degradation → inhibition of cyclin B1/Cdk1 activity → G 2 arrest is accordingly resistant to staurosporine and UCN-01 in p53 +/+ cells. Moreover, sustained phosphorylation of Chk1 in the presence of staurosporine and UCN-01 is strongly related to phosphorylation of p53. The present study suggests the unique role of Chk1 in preventing abrogation of the G 2 checkpoint in p53 +/+ cells. © 2007 by Radiation Research Society.en_US
dc.languageengen_US
dc.relation.ispartofRadiation Researchen_US
dc.titlep53-dependent Chk1 phosphorylation is required for maintenance of prolonged G 2 arresten_US
dc.typeArticleen_US
dc.identifier.emailWang, XQ: xqwang@hkucc.hku.hken_US
dc.identifier.emailFan, ST: stfan@hku.hken_US
dc.identifier.authorityWang, XQ=rp00507en_US
dc.identifier.authorityFan, ST=rp00355en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1667/RR1075.1en_US
dc.identifier.pmid18088187-
dc.identifier.scopuseid_2-s2.0-38849208560en_US
dc.identifier.hkuros140969-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-38849208560&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume168en_US
dc.identifier.issue6en_US
dc.identifier.spage706en_US
dc.identifier.epage715en_US
dc.identifier.isiWOS:000251095900008-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridWang, XQ=17343159900en_US
dc.identifier.scopusauthoridStanbridge, EJ=7103249410en_US
dc.identifier.scopusauthoridLao, X=55161053100en_US
dc.identifier.scopusauthoridCai, Q=25935876300en_US
dc.identifier.scopusauthoridFan, ST=7402678224en_US
dc.identifier.scopusauthoridRedpath, JL=7006011559en_US

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