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Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice

Oncogene volume 27, pages 5684–5695 (2008)Cite this article

Abstract

Germline mutations in the RET tyrosine kinase gene are responsible for the development of multiple endocrine neoplasia 2A and 2B (MEN2A and MEN2B). However, knowledge of the fundamental principles that determine the mutant RET-mediated signaling remains elusive. Here, we report increased expression of mitogen-activated protein kinase phosphatase-2 (MKP-2) in carcinomas developed in transgenic mice carrying RET with the MEN2A mutation (RET-MEN2A). The expression of MKP-2 was not only induced by RET-MEN2A or RET-MEN2B mutant proteins but also by the activation of endogenous RET by its ligand, glial cell line-derived neurotrophic factor (GDNF). MKP-2 expression was also evident in the MKK-f cell line, which was established from a mammary tumor developed in a RET-MEN2A transgenic mouse. Inhibition of MKP-2 attenuated the in vitro and in vivo proliferation of MKK-f cells, which was mediated by the suppression of cyclin B1 expression. Furthermore, we found that MKP-2 is highly expressed in medullary thyroid carcinomas derived from MEN2A patients. These findings suggest that the increased expression of MKP-2 may play a crucial role in oncogenic signaling downstream of mutant RET, leading to deregulation of cell cycle.

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Acknowledgements

We thank K Hirose (Nagoya University) for providing the pNAMA shRNA expression vector, S Nakamura (Nagoya University Hospital) for providing sporadic and MEN2A MTC specimens and C Suzuki (Nagoya University) and T Urano (Shimane University) for helpful discussion. We also thank Y Gotoh (Tokyo University) for providing active MAPKK (pSRα-ΔSESE-MAPKK) and MKK6 (pcDNA3.1(+)-MKK6-EE) plasmids. This study was supported by Grants-in-Aid for The 21st Century Center of Excellence (COE) Research, Scientific Research (A) and Scientific Research on Priority Area ‘Cancer’ commissioned by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (to MT).

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Authors and Affiliations

  1. Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    T Hasegawa, A Enomoto, T Kato, K Kawai, R Miyamoto, M Jijiwa, M Ishida, N Asai, Y Murakumo, K Ohara & M Takahashi

  2. Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    T Hasegawa, K Ohara, Y Niwa & H Goto

  3. Institute for Advanced Research, Nagoya University, Nagoya, Japan

    A Enomoto

  4. Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan

    M Ichihara

  5. Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

    M Takahashi

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Correspondence to M Takahashi.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Hasegawa, T., Enomoto, A., Kato, T. et al. Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice. Oncogene 27, 5684–5695 (2008). https://doi.org/10.1038/onc.2008.182

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