p21cip-1/waf-1 Deficiency Causes Deformed Nuclear Architecture, Centriole Overduplication, Polyploidy, and Relaxed Microtubule Damage Checkpoints in Human Hematopoietic Cells
- 15 February 1999
- journal article
- Published by American Society of Hematology in Blood
- Vol. 93 (4), 1390-1398
- https://doi.org/10.1182/blood.v93.4.1390
Abstract
A recent hypothesis suggests that tumor-specific killing by radiation and chemotherapy agents is due to defects or loss of cell cycle checkpoints. An important component of some checkpoints is p53-dependent induction of p21cip-1/waf-1. Both p53 and p21 have been shown to be required for microtubule damage checkpoints in mitosis and in G1 phase of the cell cycle and they thus help to maintain genetic stability. We present here evidence that p21cip-1/waf-1 deficiency relaxes the G1 phase microtubule checkpoint that is activated by microtubule damage induced with nocodazole. Reduced p21cip-1/waf-1expression also results in gross nuclear abnormalities and centriole overduplication. p53 has already been implicated in centrosome regulation. Our findings further suggest that the p53/p21 axis is involved in a checkpoint pathway that links the centriole/centrosome cycle and microtubule organization to the DNA replication cycle and thus helps to maintain genomic integrity. The inability to efficiently upregulate p21cip-1/waf-1 in p21cip-1/waf-1antisense-expressing cells in response to microtubule damage could uncouple the centrosome cycle from the DNA cycle and lead to nuclear abnormalicies and polyploidy. A centrosome duplication checkpoint could be a new target for novel chemotherapy strategies.Keywords
This publication has 17 references indexed in Scilit:
- Characterization of the p53-Dependent Postmitotic Checkpoint following Spindle DisruptionMolecular and Cellular Biology, 1998
- Cell-cycle arrest versus cell death in cancer therapyNature Medicine, 1997
- Cell Cycle Checkpoints: Preventing an Identity CrisisScience, 1996
- A p53-Dependent Mouse Spindle CheckpointScience, 1995
- The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinasesCell, 1993
- WAF1, a potential mediator of p53 tumor suppressionCell, 1993
- Creative blocks: cell-cycle checkpoints and feedback controlsNature, 1992
- Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53Cell, 1992
- Wild-type p53 is a cell cycle checkpoint determinant following irradiation.Proceedings of the National Academy of Sciences, 1992
- Checkpoints: Controls That Ensure the Order of Cell Cycle EventsScience, 1989