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A functional association between merlin and HEI10, a cell cycle regulator

Oncogene volume 25, pages 4389–4398 (2006)Cite this article

Abstract

Merlin and ezrin are homologous proteins with opposite effects on neoplastic growth. Merlin is a tumor suppressor inactivated in the neurofibromatosis 2 disease, whereas upregulated ezrin expression is associated with increased malignancy. Merlin's tumor suppressor mechanism is not known, although participation in cell cycle regulation has been suggested. To characterize merlin's biological activities, we screened for molecules that would interact with merlin but not ezrin. We identified the cyclin B-binding protein and cell cycle regulator HEI10 as a novel merlin-binding partner. The interaction is mediated by the alpha-helical domain in merlin and the coiled-coil domain in HEI10 and requires conformational opening of merlin. The two proteins show partial subcellular colocalization, which depends on cell cycle stage and cell adhesion. Comparison of Schwann cells and schwannoma cultures demonstrated that the distribution of HEI10 depends on merlin expression. In transfected cells, a constitutively open merlin construct affected HEI10 protein integrity. These results link merlin to the cell cycle control machinery and may help to understand its tumor suppressor function.

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Acknowledgements

We thank V Ramesh for the merlin 1C4 mAb, L Sherman for the RT4 and RT4-5-4 cell lines, and H Ahola, S Blomqvist, T Halmesvaara, A Partanen and M Schoultz for skillful technical assistance. This work was supported by United States Army Neurofibromatosis Research Grant DAMD17-00-0550, The Finnish Cancer Society, the Pennsylvania Tobacco Settlement Fund, Finsk-Norska Medicinska Stiftelsen and Svenska kulturfonden.

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Author notes

  1. M Grönholm and T Muranen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Neuroscience Program, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    M Grönholm, T Muranen & O Carpén

  2. Division of Basic Science, Fox Chase Cancer Center, Philadelphia, PA, USA

    G G Toby & E A Golemis

  3. Department of Neurology, University of Ulm, Ulm, Germany

    T Utermark

  4. Clinical Neurobiology, Institute of Clinical and Biomedical Science, Peninsula Medical School, Plymouth, UK

    C O Hanemann

  5. Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland

    O Carpén

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  1. M Grönholm
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  2. T Muranen
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Correspondence to M Grönholm.

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Grönholm, M., Muranen, T., Toby, G. et al. A functional association between merlin and HEI10, a cell cycle regulator. Oncogene 25, 4389–4398 (2006). https://doi.org/10.1038/sj.onc.1209475

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