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Chem Res Toxicol. 2010 Feb 15;23(2):357-64. doi: 10.1021/tx900353v.

Suppression of p53 and p21CIP1/WAF1 reduces arsenite-induced aneuploidy.

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  • 1Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico, D.F., Mexico.

Abstract

Aneuploidy and extensive chromosomal rearrangements are common in human tumors. The role of DNA damage response proteins p53 and p21(CIP1/WAF1) in aneugenesis and clastogenesis was investigated in telomerase immortalized diploid human fibroblasts using siRNA suppression of p53 and p21(CIP1/WAF1). Cells were exposed to the environmental carcinogen sodium arsenite (15 and 20 microM), and the induction of micronuclei (MN) was evaluated in binucleated cells using the cytokinesis-block assay. To determine whether MN resulted from missegregation of chromosomes or from chromosomal fragments, we used a fluorescent in situ hybridization with a centromeric DNA probe. Micronuclei were predominantly of clastogenic origin in control cells regardless of p53 or p21(CIP1/WAF1) expression. MN with centromere signals in cells transfected with NSC siRNA or Mock increased 30% after arsenite exposure, indicating that arsenite induced aneuploidy in the tGM24 cells. Although suppression of p53 increased the fraction of arsenite-treated cells with MN, it caused a decrease in the fraction with centromeric DNA. Suppression of p21(CIP1/WAF1) like p53 suppression decreased the fraction of MN with centromeric DNA. Our results suggest that cells lacking normal p53 function cannot become aneuploid because they die by mitotic arrest-associated apoptosis, whereas cells with normal p53 function that are able to exit from mitotic arrest can become aneuploid. Furthermore, our current results support this role for p21(CIP1/WAF1) since suppression of p21(CIP1/WAF1) caused a decrease in aneuploidy induced by arsenite, suggesting that p21(CIP1/WAF1) plays a role in mitotic exit.

PMID:
20000476
[PubMed - indexed for MEDLINE]
PMCID:
PMC2825144
Free PMC Article
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