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  • Original Paper
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Increased susceptibility to tumorigenesis of ski-deficient heterozygous mice

Oncogene volume 20, pages 8100–8108 (2001)Cite this article

Abstract

The c-ski proto-oncogene product (c-Ski) acts as a co-repressor and binds to other co-repressors N-CoR/SMRT and mSin3A which form a complex with histone deacetylase (HDAC). c-Ski mediates the transcriptional repression by a number of repressors, including nuclear hormone receptors and Mad. c-Ski also directly binds to, and recruits the HDAC complex to Smads, leading to inhibition of tumor growth factor-β (TGF-β) signaling. This is consistent with the function of ski as an oncogene. Here we show that loss of one copy of c-ski increases susceptibility to tumorigenesis in mice. When challenged with a chemical carcinogen, c-ski heterozygous mice showed an increased level of tumor formation relative to wild-type mice. In addition, c-ski-deficient mouse embryonic fibroblasts (MEFs) had increased proliferative capacity, whereas overexpression of c-Ski suppressed the proliferation. Furthermore, the introduction of activated Ki-ras into c-ski-deficient MEFs resulted in neoplastic transformation. These findings demonstrate that c-ski acts as a tumor suppressor in some types of cells. The level of cdc25A mRNA, which is down regulated by two tumor suppressor gene products, Rb and Mad, was upregulated in c-ski-deficient MEFs, whereas it decreased by overexpressing c-Ski in MEFs. This is consistent with the fact that c-Ski acts as a co-repressor of Mad and Rb. These results support the view that the decreased activities of Mad and Rb in ski-deficient cells at least partly contribute to enhanced proliferation and susceptibility to tumorigenesis. Human c-ski gene was mapped to a region close to the p73 tumor suppressor gene at the 1p36.3 locus, which is already known to contain multiple uncharacterized tumor suppressor genes.

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Abbreviations

c-ski:

cellular ski proto-oncogene

c-Ski:

c-ski gene product

DMBA:

9,10-dimethyl-1,2-benzanthracene

HDAC:

histone deacetylase

MEFs:

mouse embryonic fibroblasts

TGF-β:

tumor growth factor-β

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Acknowledgements

We are grateful to N Nomura for advice on mapping, M Noda for the kind gift of MuLV, and E Stavnezer for helpful discussions. This work was supported in part by grant HD30728 from the National Institutes of Health to C Colmenares.

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Authors and Affiliations

  1. Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, and CREST (Core Research for Evolutionary Science and Technology) Research Project of JST (Japan Science & Technology Corporation), 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan

    Toshie Shinagawa, Teruaki Nomura & Shunsuke Ishii

  2. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio, OH 44195, USA

    Clemencia Colmenares

  3. Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba City, Chiba, 260-8717, Japan

    Miki Ohira & Akira Nakagawara

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  1. Toshie Shinagawa
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  2. Teruaki Nomura
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  3. Clemencia Colmenares
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  4. Miki Ohira
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Correspondence to Shunsuke Ishii.

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Shinagawa, T., Nomura, T., Colmenares, C. et al. Increased susceptibility to tumorigenesis of ski-deficient heterozygous mice. Oncogene 20, 8100–8108 (2001). https://doi.org/10.1038/sj.onc.1204987

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