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Deficiency of RITA results in multiple mitotic defects by affecting microtubule dynamics

Oncogene volume 36, pages 2146–2159 (2017)Cite this article

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Abstract

Deregulation of mitotic microtubule (MT) dynamics results in defective spindle assembly and chromosome missegregation, leading further to chromosome instability, a hallmark of tumor cells. RBP-J interacting and tubulin-associated protein (RITA) has been identified as a negative regulator of the Notch signaling pathway. Intriguingly, deregulated RITA is involved in primary hepatocellular carcinoma and other malignant entities. We were interested in the potential molecular mechanisms behind its involvement. We show here that RITA binds to tubulin and localizes to various mitotic MT structures. RITA coats MTs and affects their structures in vitro as well as in vivo. Tumor cell lines deficient of RITA display increased acetylated α-tubulin, enhanced MT stability and reduced MT dynamics, accompanied by multiple mitotic defects, including chromosome misalignment and segregation errors. Re-expression of wild-type RITA, but not RITA Δtub ineffectively binding to tubulin, restores the phenotypes, suggesting that the role of RITA in MT modulation is mediated via its interaction with tubulin. Mechanistically, RITA interacts with tubulin/histone deacetylase 6 (HDAC6) and its suppression decreases the binding of the deacetylase HDAC6 to tubulin/MTs. Furthermore, the mitotic defects and increased MT stability are also observed in RITA−/− mouse embryonic fibroblasts. RITA has thus a novel role in modulating MT dynamics and its deregulation results in erroneous chromosome segregation, one of the major reasons for chromosome instability in tumor cells.

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Abbreviations

RITA:

RBP-J interacting and tubulin-associated protein

HDAC6:

histone deacetylase 6

MT:

microtubule

dSTORM:

direct stochastic optical reconstruction microscopy.

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Acknowledgements

We thank Dr L Wordeman, University of Washington, and Dr A Bird, MPI, Dortmund, Germany, for their critical manuscript reading and valuable comments. The work was supported by the Deutsche Forschungsgemeinschaft (SFB1074/A3 to FO), the BMBF (research nucleus SyStAR to FO). PK was supported by the International Graduate School in Molecular Medicine, Ulm, Germany (GSC270).

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, School of Medicine, J.W. Goethe University, Frankfurt, Germany

    K Steinhäuser, N-N Kreis, A Ritter, A Friemel, S Roth, F Louwen & J Yuan

  2. Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany

    P Klöble & F Oswald

  3. Biophysics Institute, Ulm University, Ulm, Germany

    J M Reichel & J Michaelis

  4. Department of Hematology/Oncology, J.W. Goethe University, Frankfurt, Germany

    M A Rieger

  5. German Cancer Consortium (DKTK), Heidelberg, Germany

    M A Rieger

  6. German Cancer Research Center (DKFZ), Heidelberg, Germany

    M A Rieger

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Correspondence to J Yuan.

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Steinhäuser, K., Klöble, P., Kreis, NN. et al. Deficiency of RITA results in multiple mitotic defects by affecting microtubule dynamics. Oncogene 36, 2146–2159 (2017). https://doi.org/10.1038/onc.2016.372

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