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Cyclin D1 suppresses retinoblastoma protein-mediated inhibition of TAFII250 kinase activity

Oncogene volume 19, pages 5703–5711 (2000)Cite this article

Abstract

The retinoblastoma tumor suppressor protein has been shown to bind directly and inhibit a transcriptionally-important amino-terminal kinase domain of TATA-binding protein-associated factor TAFII250. Cyclin D1 also is able to associate with the amino terminus of TAFII250 in a region very similar to or overlapping the Rb-binding site. In this study, we have examined whether cyclin D1 affects the functional interaction between Rb and TAFII250. We observed that when cyclin D1 is co-incubated with Rb and TAFII250, the ability of Rb to inhibit TAFII250 kinase activity is effectively blocked. However, cyclin D1 by itself has no apparent effect on TAFII250 kinase activity. We further found that the Rb-related protein p107 can inhibit TAFII250 kinase activity, and this inhibition is likewise alleviated by cyclin D1. Cyclin D1 prevents the kinase-inhibitory effect of an Rb mutant unable to bind to D-type cyclins, indicating that it is acting through its association with TAFII250 and not with Rb. However, we found no evidence of TAFII250-binding competition between Rb and cyclin D1 in vitro. The adenovirus E1A protein, which also binds to both Rb and TAFII250, exhibited a suppressive effect on Rb-mediated kinase inhibition similar to that seen with cyclin D1. Our results suggest a novel means by which cyclin D1 may be able to independently regulate the activity of Rb.

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Acknowledgements

This work was supported by a public health service grant (55227) from the National Cancer Institute to PD Robbins and by a predoctoral research training grant from the United States Army to JL Siegert. We thank Z Shao and J Adnane for reagents and critical work leading up to this study. We would also like to thank M Ewen and C McMahon for kindly providing the cyclin D1 baculovirus, R Tjian and S Ruppert for providing TAFII250 expression constructs, Z Burton and L Lei for the RAP74 construct, and D Rowe for supplying the E1A construct.

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  1. John J Rushton

    Present address: Department of Molecular Genetics and Microbiology, 125 Cancer Research Center, University of New Mexico School of Medicine, Albuquerque, 87131, New Mexico, USA

Authors and Affiliations

  1. Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, Pennsylvania, USA

    Jennifer L Siegert, John J Rushton & Paul D Robbins

  2. Department of Adult Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, Massachusetts, USA

    William R Sellers & William G Kaelin Jr

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  1. Jennifer L Siegert
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Siegert, J., Rushton, J., Sellers, W. et al. Cyclin D1 suppresses retinoblastoma protein-mediated inhibition of TAFII250 kinase activity. Oncogene 19, 5703–5711 (2000). https://doi.org/10.1038/sj.onc.1203966

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