Abstract
Tumorigenesis is a consequence of loss of tumor suppressors and activation of oncogenes. Expression of the mitotic checkpoint protein Chfr is lost in 20-50% of primary tumors and tumor cell lines. To explore whether downregulation of Chfr contributes directly to tumorigenesis, we generated Chfr knockout mice. Chfr-deficient mice are cancer-prone, develop spontaneous tumors and have increased skin tumor incidence after treatment with dimethylbenz(a)anthracene. Chfr deficiency leads to chromosomal instability in embryonic fibroblasts and regulates the mitotic kinase Aurora A, which is frequently upregulated in a variety of tumors. Chfr physically interacts with Aurora A and ubiquitinates Aurora A both in vitro and in vivo. Collectively, our data suggest that Chfr is a tumor suppressor and ensures chromosomal stability by controlling the expression levels of key mitotic proteins such as Aurora A.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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9,10-Dimethyl-1,2-benzanthracene / toxicity
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Animals
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Aurora Kinase A
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Aurora Kinases
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Carcinogens / toxicity
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Chromosomal Instability
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Embryo, Mammalian / cytology
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Embryo, Mammalian / enzymology
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Female
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Fibroblasts / enzymology
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Gene Expression Regulation, Neoplastic*
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Gene Targeting
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Genes, Tumor Suppressor / physiology*
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Heterozygote
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Homozygote
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Male
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Mice
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Mice, Knockout
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Mitosis / genetics
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Poly-ADP-Ribose Binding Proteins
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases
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Skin Neoplasms / chemically induced
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Skin Neoplasms / genetics*
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Skin Neoplasms / pathology
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases
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Xenopus Proteins
Substances
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Carcinogens
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Cell Cycle Proteins
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Neoplasm Proteins
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Poly-ADP-Ribose Binding Proteins
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Ubiquitin
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Xenopus Proteins
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9,10-Dimethyl-1,2-benzanthracene
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CHFR protein, human
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Ubiquitin-Protein Ligases
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Protein Kinases
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AURKA protein, Xenopus
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Aurka protein, mouse
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Aurora Kinase A
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Aurora Kinases
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Protein Serine-Threonine Kinases