Requirement for p53 and p21 to sustain G2 arrest after DNA damage.

After DNA damage, many cells appear to enter a sustained arrest in the G2 phase of the cell cycle. It is shown here that this arrest could be sustained only when p53 was present in the cell and capable of transcriptionally activating the cyclin-dependent kinase inhibitor p21. After disruption of either the p53 or the p21 gene, gamma radiated cells progressed into mitosis and exhibited a G2 DNA content only because of a failure of cytokinesis. Thus, p53 and p21 appear to be essential for maintaining the G2 checkpoint in human cells.

[1]  G. Hicks,et al.  Evidence for a second cell cycle block at G2/M by p53. , 1995, Oncogene.

[2]  S. Reed,et al.  Nuclear Accumulation of p21Cip1 at the Onset of Mitosis: a Role at the G2/M-Phase Transition , 1998, Molecular and Cellular Biology.

[3]  W. B. Smith,et al.  A Role for Endothelial NO Synthase in LTP Revealed by Adenovirus-Mediated Inhibition and Rescue , 1996, Science.

[4]  K. Kinzler,et al.  14-3-3σ Is a p53-Regulated Inhibitor of G2/M Progression , 1997 .

[5]  Bert Vogelstein,et al.  Mutations of mitotic checkpoint genes in human cancers , 1998, Nature.

[6]  R. Muschel,et al.  The molecular basis for cell cycle delays following ionizing radiation: a review. , 1994, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[7]  J. Cooper,et al.  A cytokinesis checkpoint requiring the yeast homologue of an APC-binding protein , 1998, Nature.

[8]  T. Jacks,et al.  Characterization of the p53-Dependent Postmitotic Checkpoint following Spindle Disruption , 1998, Molecular and Cellular Biology.

[9]  K. Vousden,et al.  Cell cycle arrest and DNA endoreduplication following p21Waf1/Cip1 expression , 1998, Oncogene.

[10]  S. Friend,et al.  Differential sensitivity of p53(-) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. , 1995, Cancer research.

[11]  C. Peng,et al.  Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. , 1997, Science.

[12]  A. Levine p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[13]  David Beach,et al.  p21 is a universal inhibitor of cyclin kinases , 1993, Nature.

[14]  S. Elledge,et al.  Inhibition of cyclin-dependent kinases by p21. , 1995, Molecular biology of the cell.

[15]  B. Vogelstein,et al.  Participation of p53 protein in the cellular response to DNA damage. , 1991, Cancer research.

[16]  D. Givol,et al.  Induction of WAF1/CIP1 by a p53-independent pathway. , 1994, Cancer research.

[17]  M. Bornens,et al.  Organisation and functional regulation of the centrosome in animal cells. , 1997, Progress in cell cycle research.

[18]  G. Woude,et al.  Abnormal Centrosome Amplification in the Absence of p53 , 1996, Science.

[19]  T. Guadagno,et al.  Cdk2 Kinase Is Required for Entry into Mitosis as a Positive Regulator of Cdc2–Cyclin B Kinase Activity , 1996, Cell.

[20]  K. Kohn,et al.  Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. , 1995, Cancer research.

[21]  R. Paules,et al.  Inactivation of G2 checkpoint function and chromosomal destabilization are linked in human fibroblasts expressing human papillomavirus type 16 E6. , 1997, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[22]  L. Hartwell,et al.  Cell cycle control and cancer. , 1994, Science.

[23]  L. Hengst,et al.  Effects of p21Cip1/Waf1 at Both the G1/S and the G2/M Cell Cycle Transitions: pRb Is a Critical Determinant in Blocking DNA Replication and in Preventing Endoreduplication , 1998, Molecular and Cellular Biology.

[24]  James Brugarolas,et al.  Radiation-induced cell cycle arrest compromised by p21 deficiency , 1995, Nature.

[25]  P. Olive,et al.  Development of apoptosis and polyploidy in human lymphoblast cells as a function of position in the cell cycle at the time of irradiation. , 1996, Radiation research.

[26]  G. Stark,et al.  p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Wenyi Wei,et al.  Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. , 1997, Science.

[28]  Y. Xiong,et al.  Cell cycle expression and p53 regulation of the cyclin-dependent kinase inhibitor p21. , 1994, Oncogene.

[29]  Stephen J. Elledge,et al.  Mice Lacking p21 CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control , 1995, Cell.

[30]  D. Payan,et al.  Identification of a nuclear-specific cyclophilin which interacts with the proteinase inhibitor eglin c. , 1996, Biochemical Journal.

[31]  C. Smythe,et al.  Coupling of mitosis to the completion of S phase in Xenopus occurs via modulation of the tyrosine kinase that phosphorylates p34 cdc2 , 1992, Cell.

[32]  K. Kinzler,et al.  p21 is necessary for the p53-mediated G1 arrest in human cancer cells. , 1995, Cancer research.

[33]  D. Görlich,et al.  Regulatory roles of the nuclear envelope. , 1996, Experimental cell research.

[34]  G. Wahl,et al.  p53 and pRb prevent rereplication in response to microtubule inhibitors by mediating a reversible G1 arrest. , 1998, Cancer research.

[35]  A. Moustakas,et al.  Regulation of the human p21/WAF1/Cip1 promoter in hepatic cells by functional interactions between Sp1 and Smad family members. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  K. Kinzler,et al.  p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. , 1995, Genes & development.

[37]  K. Kinzler,et al.  Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues. , 1995, Cancer research.

[38]  C. Prives,et al.  p53: puzzle and paradigm. , 1996, Genes & development.

[39]  L. Hartwell,et al.  Integrating genetic approaches into the discovery of anticancer drugs. , 1997, Science.

[40]  K. Kinzler,et al.  Targeted deletion of Smad4 shows it is required for transforming growth factor beta and activin signaling in colorectal cancer cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[41]  M. Kirschner,et al.  Geminin, an Inhibitor of DNA Replication, Is Degraded during Mitosis , 1998, Cell.

[42]  Bert Vogelstein,et al.  Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21 , 1996, Nature.

[43]  M. Kirschner,et al.  Role of phosphorylation in p34cdc2 activation: identification of an activating kinase. , 1992, Molecular biology of the cell.

[44]  D. Lane,et al.  Tumour suppressors, kinases and clamps: How p53 regulates the cell cycle in response to DNA damage , 1995, BioEssays : news and reviews in molecular, cellular and developmental biology.