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A retinoblastoma-binding protein that affects cell-cycle control and confers transforming ability

Nature Genetics volume 19, pages 371–374 (1998)Cite this article

Abstract

The retinoblastoma (RB) gene is one of the most extensively studied tumour-suppressor genes1. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma that arise in families that carry mutant RB (ref. 2). RB inactivation is also found in other human tumours3,4,5,6,7,8. Whereas loss of RB function is associated with the loss of cellular proliferative control, introduction of a wild-type RB can suppress cell growth and tumorigenicity5,9,10,11,12. Thus, identification of factors that interfere with and/or control the function of the RB protein is critical for understanding both cell-cycle control and oncogenesis. Here we describe a new gene, Bog (for B5T over-expressed gene), which was identified and shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-ß1, as well as in primary human liver tumours. The Bog protein shares homology with other retinoblastoma-binding proteins and contains the Rb-binding motif LXCXE. Using the yeast two-hybrid system and co-immunoprecipitation, we demonstrated that Bog binds to Rb. In vivo, Bog/Rb complexes do not contain E2F-1, and Bog can displace E2F-1 from E2F-1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-ß1. Furthermore, normal RLE cells are rapidly transformed when Bog is continuously overexpressed and form hepatoblastoma-like tumours when transplanted into nude mice. These data suggest that Bog may be important in the transformation process, in part due to its capacity to confer resistance to the growth-inhibitory effects of TGF-ß1 through interaction with Rb and the subsequent displacement of E2F-1.

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Figure 1: Sequence and sequence homology of Bog.
Figure 2: Demonstration of Rb and Bog interaction.
Figure 3: Constitutive overexpression of Bog disrupts the growth-inhibitory effect of TGF-ß1.
Figure 4: Increased expression of Bog correlates with transformation.

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Acknowledgements

We would like to thank V. Factor and P.J. Wirth for their review and comments, and R. Hong for his assistance in the laboratory.

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    Authors and Affiliations

    1. Division of Basic Sciences, Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, 20892-4255, Maryland, USA

      Joseph T. Woitach, Minghuang Zhang & Snorri S. Thorgeirsson

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    Correspondence to Snorri S. Thorgeirsson.

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    Woitach, J., Zhang, M., Niu, CH. et al. A retinoblastoma-binding protein that affects cell-cycle control and confers transforming ability. Nat Genet 19, 371–374 (1998). https://doi.org/10.1038/1258

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