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

  1. Author:
    Fan, T.
    Yan, Q. S.
    Huang, J. Q.
    Austin, S.
    Cho, E.
    Ferris, D.
    Muegge, K.

  2. Author Address

    NCI, Mol Immunoregulat Lab, Basic Res Program, SAIC Frederick, Bldg 469,Room 243, Frederick, MD 21701 USA NCI, Mol Immunoregulat Lab, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA NCI, Lab Leukocyte Biol, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA NCI, Image Anal Lab, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA NCI, Basic Res Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA Muegge K NCI, Mol Immunoregulat Lab, Basic Res Program, SAIC Frederick, Bldg 469,Room 243, Frederick, MD 21701 USA
    1. Year: 2003
  2. Journal: Cancer Research
    1. 63
    2. 15
    3. Pages: 4677-4683
  4. Type of Article: Article
  1. 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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