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Control of microtubule stability by the RASSF1A tumor suppressor

Oncogene volume 22, pages 8125–8136 (2003)Cite this article

Abstract

The RAS association domain family 1A (RASSF1A) gene is silenced by DNA methylation in over 50% of all solid tumors of different histological types. However, the biochemical function of the RASSF1A protein is unknown. We show that RASSF1A colocalizes with microtubules in interphase and decorates spindles and centrosomes during mitosis. RASSF1A has a strong cytoprotective activity against the microtubule-destabilizing drug nocodazole, and against cold-treatment in vivo. Conversely, loss of RASSF1 in RASSF1−/− mouse embryonic fibroblasts renders the cells more sensitive to nocodazole-induced depolymerization of microtubules. The domain required for both microtubule association and stabilization was mapped to a 169 amino-acid fragment that contains the RAS association domain. Overexpression of RASSF1A induces mitotic arrest at metaphase with aberrant mitotic cells reminiscent of such produced by the microtubule-stabilizing drug paclitaxel (taxol), including monopolar spindles, or complete lack of a mitotic spindle. Altered microtubule stability in cells lacking RASSF1A is likely to affect spindle assembly and chromosome attachment, processes that need to be carefully controlled to protect cells from genomic instability and transformation. In addition, knowledge of the microtubule-targeting function of RASSF1 may aid in the development of new anticancer drugs.

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Abbreviations

DAPI:

4,6-diamidino-2-phenylindole

MEF:

mouse embryonic fibroblast

MTOC:

microtubule-organizing center

RASSF1A:

RAS association domain family 1A

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Acknowledgements

We thank R Barber, M Lee, and P Salvaterra for assistance with microscopy, S Bates for culturing cells, W Tsark and F Silva for ES cell electroporation and blastocyst injection, L Brown and C Spalla for FACS analysis, S-G Jin for plasmid construction, and J Shively, CJ Chen, and CL Jiang for instructive discussions. This work was supported by NIH Grant CA88873 (to GPP) and by BMBF Grant FKZ01ZZ0104 (to RD).

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Authors and Affiliations

  1. Division of Biology, Beckman Research Institute of the City of Hope,

    Limin Liu, Stella Tommasi, Dong-Hyun Lee & Gerd P Pfeifer

  2. Duarte, 91010, CA, USA

    Limin Liu, Stella Tommasi, Dong-Hyun Lee & Gerd P Pfeifer

  3. Institut für Humangenetik und Medizinische Biologie, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, D-06097, Germany

    Reinhard Dammann

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Correspondence to Gerd P Pfeifer.

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Liu, L., Tommasi, S., Lee, DH. et al. Control of microtubule stability by the RASSF1A tumor suppressor. Oncogene 22, 8125–8136 (2003). https://doi.org/10.1038/sj.onc.1206984

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