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

T. Hasegawa, A. Enomoto, T. Kato, K. Kawai, R. Miyamoto, M. Jijiwa, M. Ichihara, M. Ishida, N. Asai, Y. Murakumo, K. Ohara, Y. Niwa, H. Goto, M. Takahashi

研究成果: Article査読

24 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)5684-5695
ページ数12
ジャーナルOncogene
27
43
DOI
出版ステータスPublished - 25-09-2008
外部発表はい

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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