p21(cip-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, Hal Broxmeyer

Research output: Contribution to journalArticle

113 Citations (Scopus)

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 p21(cip-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 p21(cip-1/waf-1) deficiency relaxes the G1 phase microtubule checkpoint that is activated by microtubule damage induced with nocodazole. Reduced p21(cip-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 p21(cip- 1/waf-1) in p21(cip-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.

Original languageEnglish (US)
Pages (from-to)1390-1398
Number of pages9
JournalBlood
Volume93
Issue number4
StatePublished - Feb 15 1999
Externally publishedYes

Fingerprint

Centrioles
Polyploidy
Chemotherapy
Centrosome
Microtubules
Cells
Nocodazole
DNA
Tumors
Radiation
Defects
G1 Phase Cell Cycle Checkpoints
Drug Therapy
G1 Phase
Cell Cycle Checkpoints
DNA Replication
Mitosis
Cell Cycle
Up-Regulation
Neoplasms

ASJC Scopus subject areas

  • Hematology

Cite this

p21(cip-1/waf-1) deficiency causes deformed nuclear architecture, centriole overduplication, polyploidy, and relaxed microtubule damage checkpoints in human hematopoietic cells. / Mantel, Charlie; Braun, Stephen E.; Reid, Suzanna; Henegariu, Octavian; Liu, Lisa; Hangoc, Giao; Broxmeyer, Hal.

In: Blood, Vol. 93, No. 4, 15.02.1999, p. 1390-1398.

Research output: Contribution to journalArticle

Mantel, Charlie ; Braun, Stephen E. ; Reid, Suzanna ; Henegariu, Octavian ; Liu, Lisa ; Hangoc, Giao ; Broxmeyer, Hal. / p21(cip-1/waf-1) deficiency causes deformed nuclear architecture, centriole overduplication, polyploidy, and relaxed microtubule damage checkpoints in human hematopoietic cells. In: Blood. 1999 ; Vol. 93, No. 4. pp. 1390-1398.
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