Lsh-deficient murine embryonal fibroblasts show reduced proliferation with signs of abnormal mitosis - PubMed (original) (raw)

. 2003 Aug 1;63(15):4677-83.

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Lsh-deficient murine embryonal fibroblasts show reduced proliferation with signs of abnormal mitosis

Tao Fan et al. Cancer Res. 2003.

Abstract

Genomic hypomethylation and chromosomal instability are frequent characteristics of human cancer cells. Targeted deletion of Lsh leads to a global defect in genomic methylation, and Lsh-deficient mice die at birth with a reduced body weight. Here, we examine the growth pattern of embryonal fibroblasts derived from Lsh-/- mice. The absence of Lsh leads to a severe proliferative defect of fibroblasts with lower saturation density, early signs of senescence, and a lower frequency of immortalization. The impaired growth rate in vitro may be in part responsible for the small size of Lsh-deficient mice. In addition, Lsh-/- fibroblasts accumulated high centrosome numbers, formed multipolar spindles, displayed micronuclei formation, and elevated nuclear DNA content. A similar increase in centrosome abnormalities was observed when wild-type fibroblasts were treated with a DNA-demethylating agent, suggesting that genomic hypomethylation plays an important role in mitotic defects of Lsh-/- murine embryonal fibroblasts, possibly by altering chromatin structure. Because supernumerary centrosomes are a common feature in cancer cells, this Lsh-dependent pathway has the potential to contribute to genetic instability and chromosomal aberrations during tumor progression.

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