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Article: Complexity of the mechanisms of initiation and maintenance of DNA damage-induced G 2-phase arrest and subsequent G 1-phase arrest: TP53-dependent and TP53-independent roles

TitleComplexity of the mechanisms of initiation and maintenance of DNA damage-induced G 2-phase arrest and subsequent G 1-phase arrest: TP53-dependent and TP53-independent roles
Authors
Issue Date2003
Citation
Radiation Research, 2003, v. 159 n. 1, p. 72-85 How to Cite?
AbstractThrough a detailed study of cell cycle progression, protein expression, and kinase activity in γ-irradiated synchronized cultures of human skin fibroblasts, distinct mechanisms of initiation and maintenance of G 2-phase and subsequent G 1-phase arrests have been elucidated. Normal and E6-expressing fibroblasts were used to examine the role of TP53 in these processes. While G 2 arrest is correlated with decreased cyclin B1/CDC2 kinase activity, the mechanisms associated with initiation and maintenance of the arrest are quite different. Initiation of the transient arrest is TP53-independent and is due to inhibitory phosphorylation of CDC2 at Tyr15. Maintenance of the G 2 arrest is dependent on TP53 and is due to decreased levels of cyclin B1 mRNA and a corresponding decline in cyclin B1 protein level. After transiently arresting in G 2 phase, normal cells chronically arrest in the subsequent G 1 phase while E6-expressing cells continue to cycle. The initiation of this TP53-dependent G 1-phase arrest occurs despite the presence of substantial levels of cyclin D1/CDK4 and cyclin E/CDK2 kinase activities, hyperphosphoryated RB, and active E2F1. CDKN1A (also known as p21 WAFI/CIPI) levels remain elevated during this period. Furthermore, CDKN1A-dependent inhibition of PCNA activity does not appear to be the mechanism for this early G 1 arrest. Thus the inhibition of entry of irradiated cells into S phase does not appear to be related to DNA-bound PCNA complexed to CDKN1A. The mechanism of chronic G 1 arrest involves the down-regulation of specific proteins with a resultant loss of cyclin E/CDK2 kinase activity. © 2003 by Radiation Research Society.
Persistent Identifierhttp://hdl.handle.net/10722/172816
ISSN
2015 Impact Factor: 3.022
2015 SCImago Journal Rankings: 1.493
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorDesimone, JNen_US
dc.contributor.authorBengtsson, Uen_US
dc.contributor.authorWang, XQen_US
dc.contributor.authorLao, XYen_US
dc.contributor.authorRedpath, JLen_US
dc.contributor.authorStanbridge, EJen_US
dc.date.accessioned2012-10-30T06:25:05Z-
dc.date.available2012-10-30T06:25:05Z-
dc.date.issued2003en_US
dc.identifier.citationRadiation Research, 2003, v. 159 n. 1, p. 72-85en_US
dc.identifier.issn0033-7587en_US
dc.identifier.urihttp://hdl.handle.net/10722/172816-
dc.description.abstractThrough a detailed study of cell cycle progression, protein expression, and kinase activity in γ-irradiated synchronized cultures of human skin fibroblasts, distinct mechanisms of initiation and maintenance of G 2-phase and subsequent G 1-phase arrests have been elucidated. Normal and E6-expressing fibroblasts were used to examine the role of TP53 in these processes. While G 2 arrest is correlated with decreased cyclin B1/CDC2 kinase activity, the mechanisms associated with initiation and maintenance of the arrest are quite different. Initiation of the transient arrest is TP53-independent and is due to inhibitory phosphorylation of CDC2 at Tyr15. Maintenance of the G 2 arrest is dependent on TP53 and is due to decreased levels of cyclin B1 mRNA and a corresponding decline in cyclin B1 protein level. After transiently arresting in G 2 phase, normal cells chronically arrest in the subsequent G 1 phase while E6-expressing cells continue to cycle. The initiation of this TP53-dependent G 1-phase arrest occurs despite the presence of substantial levels of cyclin D1/CDK4 and cyclin E/CDK2 kinase activities, hyperphosphoryated RB, and active E2F1. CDKN1A (also known as p21 WAFI/CIPI) levels remain elevated during this period. Furthermore, CDKN1A-dependent inhibition of PCNA activity does not appear to be the mechanism for this early G 1 arrest. Thus the inhibition of entry of irradiated cells into S phase does not appear to be related to DNA-bound PCNA complexed to CDKN1A. The mechanism of chronic G 1 arrest involves the down-regulation of specific proteins with a resultant loss of cyclin E/CDK2 kinase activity. © 2003 by Radiation Research Society.en_US
dc.languageengen_US
dc.relation.ispartofRadiation Researchen_US
dc.subject.meshCell Cycle - Radiation Effectsen_US
dc.subject.meshCell Lineen_US
dc.subject.meshDna Damageen_US
dc.subject.meshDna Primersen_US
dc.subject.meshFibroblasts - Radiation Effectsen_US
dc.subject.meshG1 Phase - Physiology - Radiation Effectsen_US
dc.subject.meshG2 Phase - Physiology - Radiation Effectsen_US
dc.subject.meshGamma Raysen_US
dc.subject.meshGenes, P53en_US
dc.subject.meshHumansen_US
dc.subject.meshKineticsen_US
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen_US
dc.subject.meshSkin - Radiation Effectsen_US
dc.subject.meshTumor Suppressor Protein P53 - Geneticsen_US
dc.titleComplexity of the mechanisms of initiation and maintenance of DNA damage-induced G 2-phase arrest and subsequent G 1-phase arrest: TP53-dependent and TP53-independent rolesen_US
dc.typeArticleen_US
dc.identifier.emailWang, XQ: xqwang@hkucc.hku.hken_US
dc.identifier.authorityWang, XQ=rp00507en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1667/0033-7587(2003)159[0072:COTMOI]2.0.CO;2en_US
dc.identifier.pmid12492370-
dc.identifier.scopuseid_2-s2.0-0037225464en_US
dc.identifier.hkuros94322-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0037225464&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume159en_US
dc.identifier.issue1en_US
dc.identifier.spage72en_US
dc.identifier.epage85en_US
dc.identifier.isiWOS:000180260800008-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridDeSimone, JN=8785956200en_US
dc.identifier.scopusauthoridBengtsson, U=7005608839en_US
dc.identifier.scopusauthoridWang, XQ=17343159900en_US
dc.identifier.scopusauthoridLao, XY=55161053100en_US
dc.identifier.scopusauthoridRedpath, JL=7006011559en_US
dc.identifier.scopusauthoridStanbridge, EJ=7103249410en_US

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