In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. LB-188-LB-188
Abstract:
Many checkpoint-deficient cancer cells are unable to maintain a numerically stable chromosome complement. The Chk1 kinase has a well-established role in the DNA damage checkpoint responses and is also essential for viability; however little is known about its role throughout the unperturbed cell cycle. Here, we rigorously examine the role of Chk1 in the maintenance of cell ploidy and mitotic progression. Using recombinant adeno-associated virus-based gene targeting techniques, we disrupted one allele of CHK1 in human cancer cell lines that are proficient or deficient for the tumor suppressor p53. We assessed ploidy by fluorescence in situ hybridization and metaphase chromosome analysis, and examined cell cycle progression by live cell time-lapse fluorescent microscopy, DNA labeling, flow cytometry and biochemical analysis. Loss of one CHK1 allele caused an elevated frequency of mitotic bypass in p53-deficient cells. CHK1-haploinsufficient, p53-deficient cells frequently underwent sequential rounds of DNA synthesis without an intervening mitosis, which caused whole genome endoreduplication and tetraploidization. CHK1 haploinsufficient cells exhibited reduced Cdk1 activity, which has been shown to lead to the bypass of mitosis. This mitotic bypass phenotype could be suppressed by targeted reversion of a p53 mutation or by exogenous Cdk1 expression. Interestingly, the rate of mitotic bypass was independent of upstream signaling by ATR to Chk1 and was not associated with DNA damage. These findings demonstrate a previously unrecognized role for Chk1 in promoting the initiation of mitosis during the cancer cell cycle and thereby maintaining ploidy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-188. doi:10.1158/1538-7445.AM2011-LB-188
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-LB-188
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
