Access

You are not currently logged in.

Access your personal account or get JSTOR access through your library or other institution:

login

Log in to your personal account or through your institution.

If You Use a Screen Reader

This content is available through Read Online (Free) program, which relies on page scans. Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.

Complexity of the Mechanisms of Initiation and Maintenance of DNA Damage-Induced ${\rm G}_{2}\text{-Phase}$ Arrest and Subsequent ${\rm G}_{1}\text{-Phase}$ Arrest: TP53-Dependent and TP53-Independent Roles

John N. DeSimone, Ulla Bengtsson, XiaoQi Wang, Xiao Yan Lao, J. Leslie Redpath and Eric J. Stanbridge
Radiation Research
Vol. 159, No. 1 (Jan., 2003), pp. 72-85
Stable URL: http://www.jstor.org/stable/3580752
Page Count: 14
  • Read Online (Free)
  • Download ($10.00)
  • Subscribe ($19.50)
  • Cite this Item
Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Complexity of the Mechanisms of Initiation and Maintenance of DNA Damage-Induced ${\rm G}_{2}\text{-Phase}$ Arrest and Subsequent ${\rm G}_{1}\text{-Phase}$ Arrest: TP53-Dependent and TP53-Independent Roles
Preview not available

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 G2-phase and subsequent G1-phase arrests have been elucidated. Normal and E6-expressing fibroblasts were used to examine the role of TP53 in these processes. While G2 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 G2 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 G2 phase, normal cells chronically arrest in the subsequent G1 phase while E6-expressing cells continue to cycle. The initiation of this TP53-dependent G1-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 WAF1/ CIP1) levels remain elevated during this period. Furthermore, CDKN1A-dependent inhibition of PCNA activity does not appear to be the mechanism for this early G1 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 G1 arrest involves the down-regulation of specific proteins with a resultant loss of cyclin E/CDK2 kinase activity.

Page Thumbnails

  • Thumbnail: Page 
72
    72
  • Thumbnail: Page 
73
    73
  • Thumbnail: Page 
74
    74
  • Thumbnail: Page 
75
    75
  • Thumbnail: Page 
76
    76
  • Thumbnail: Page 
77
    77
  • Thumbnail: Page 
78
    78
  • Thumbnail: Page 
79
    79
  • Thumbnail: Page 
80
    80
  • Thumbnail: Page 
81
    81
  • Thumbnail: Page 
82
    82
  • Thumbnail: Page 
83
    83
  • Thumbnail: Page 
84
    84
  • Thumbnail: Page 
85
    85