Inhibition of oncogenic transformation by mammalian Lin-9, a pRB-associated protein

Authors

  • Sladjana Gagrica,

    1. Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Marburg, Germany
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    • These authors contributed equally to this work
  • Stefanie Hauser,

    1. Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Marburg, Germany
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    • These authors contributed equally to this work
  • Ingrid Kolfschoten,

    1. Division of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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  • Lisa Osterloh,

    1. Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Marburg, Germany
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  • Reuven Agami,

    1. Division of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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  • Stefan Gaubatz

    Corresponding author
    1. Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Marburg, Germany
    • Corresponding author. Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Emil-Mannkopffstr. 2, 35037 Marburg, Germany. Tel.: +49 6421 2866240; Fax: +49 6421 2867008; E-mail: gaubatz@imt.uni-marburg.de

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Abstract

Genetic studies in Caenorhabditis elegans identified lin-9 to function together with the retinoblastoma homologue lin-35 in vulva differentiation. We have now identified a human homologue of Lin-9 (hLin-9) and provide evidence about its function in the mammalian pRB pathway. hLin-9 binds to pRB and cooperates with pRB in flat cell formation in Saos-2 cells. In addition, hLin-9 synergized with pRB and Cbfal to transactivate an osteoblast-specific reporter gene. In contrast, hLin-9 was not involved in pRB-mediated inhibition of cell cycle progression or repression of E2F-dependent transactivation. Consistent with these data, hLin-9 was able to associate with partially penetrant pRB mutants that do not bind to E2F, but retain the ability to activate transcription and to promote differentiation. hLin-9 can also inhibit oncogenic transformation, dependent on the presence of a functional pRB protein. RNAi-mediated knockdown of Lin-9 can substitute for the loss of pRB in transformation of human primary fibroblasts. These data suggest that hLin-9 has tumor-suppressing activities and that the ability of hLin-9 to inhibit transformation is mediated through its association with pRB.

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