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- Publisher Website: 10.1667/0033-7587(2003)159[0072:COTMOI]2.0.CO;2
- Scopus: eid_2-s2.0-0037225464
- PMID: 12492370
- WOS: WOS:000180260800008
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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
Title | 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 |
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Authors | |
Issue Date | 2003 |
Citation | Radiation Research, 2003, v. 159 n. 1, p. 72-85 How to Cite? |
Abstract | Through 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 Identifier | http://hdl.handle.net/10722/172816 |
ISSN | 2023 Impact Factor: 2.5 2023 SCImago Journal Rankings: 0.695 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Desimone, JN | en_US |
dc.contributor.author | Bengtsson, U | en_US |
dc.contributor.author | Wang, XQ | en_US |
dc.contributor.author | Lao, XY | en_US |
dc.contributor.author | Redpath, JL | en_US |
dc.contributor.author | Stanbridge, EJ | en_US |
dc.date.accessioned | 2012-10-30T06:25:05Z | - |
dc.date.available | 2012-10-30T06:25:05Z | - |
dc.date.issued | 2003 | en_US |
dc.identifier.citation | Radiation Research, 2003, v. 159 n. 1, p. 72-85 | en_US |
dc.identifier.issn | 0033-7587 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/172816 | - |
dc.description.abstract | Through 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.language | eng | en_US |
dc.relation.ispartof | Radiation Research | en_US |
dc.subject.mesh | Cell Cycle - Radiation Effects | en_US |
dc.subject.mesh | Cell Line | en_US |
dc.subject.mesh | Dna Damage | en_US |
dc.subject.mesh | Dna Primers | en_US |
dc.subject.mesh | Fibroblasts - Radiation Effects | en_US |
dc.subject.mesh | G1 Phase - Physiology - Radiation Effects | en_US |
dc.subject.mesh | G2 Phase - Physiology - Radiation Effects | en_US |
dc.subject.mesh | Gamma Rays | en_US |
dc.subject.mesh | Genes, P53 | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Kinetics | en_US |
dc.subject.mesh | Reverse Transcriptase Polymerase Chain Reaction | en_US |
dc.subject.mesh | Skin - Radiation Effects | en_US |
dc.subject.mesh | Tumor Suppressor Protein P53 - Genetics | en_US |
dc.title | 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 | en_US |
dc.type | Article | en_US |
dc.identifier.email | Wang, XQ: xqwang@hkucc.hku.hk | en_US |
dc.identifier.authority | Wang, XQ=rp00507 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1667/0033-7587(2003)159[0072:COTMOI]2.0.CO;2 | en_US |
dc.identifier.pmid | 12492370 | - |
dc.identifier.scopus | eid_2-s2.0-0037225464 | en_US |
dc.identifier.hkuros | 94322 | - |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-0037225464&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 159 | en_US |
dc.identifier.issue | 1 | en_US |
dc.identifier.spage | 72 | en_US |
dc.identifier.epage | 85 | en_US |
dc.identifier.isi | WOS:000180260800008 | - |
dc.publisher.place | United States | en_US |
dc.identifier.scopusauthorid | DeSimone, JN=8785956200 | en_US |
dc.identifier.scopusauthorid | Bengtsson, U=7005608839 | en_US |
dc.identifier.scopusauthorid | Wang, XQ=17343159900 | en_US |
dc.identifier.scopusauthorid | Lao, XY=55161053100 | en_US |
dc.identifier.scopusauthorid | Redpath, JL=7006011559 | en_US |
dc.identifier.scopusauthorid | Stanbridge, EJ=7103249410 | en_US |
dc.identifier.issnl | 0033-7587 | - |