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Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1390-1398
p21cip-1/waf-1 Deficiency Causes Deformed Nuclear
Architecture, Centriole Overduplication, Polyploidy, and Relaxed
Microtubule Damage Checkpoints in Human Hematopoietic Cells
Charlie Mantel,
Stephen E. Braun,
Suzanna Reid,
Octavian Henegariu,
Lisa Liu,
Giao Hangoc, and
Hal E. Broxmeyer
From the Departments of Microbiology/Immunology, Medical and
Molecular Genetics, Medicine, and the Walther Oncology Center, Indiana
University School of Medicine, Indianapolis, IN; and the Walther Cancer
Institute, Indianapolis, IN.
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-1
expression 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-1
antisense-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.
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