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Nore1 inhibits tumor cell growth independent of Ras or the MST1/2 kinases

Oncogene volume 23, pages 3426–3433 (2004)Cite this article

Abstract

Nore1, a noncatalytic protein identified by its ability to bind selectively to active Ras, is most closely related in amino-acid sequence to the tumor suppressor RASSF1. Both are expressed predominantly as a longer (Nore1A/RASSF1A) and/or shorter (Nore1B/RASSF1C) polypeptide; all four polypeptides contain a Ras-association domain and bind, through their conserved carboxytermini, the proapoptotic protein kinases MST1 and MST2. Moreover, the expression of the longer polypeptide is downregulated in human tumor cell lines through promoter methylation (frequently for RASSF1A, less regularly for Nore1A). Forced expression of RASSF1A in several such lines (including the NSCLC line A549) has been shown to suppress tumorigenicity; herein we inquire whether Nore has growth inhibitory activity. Four tumor cell lines were tested, selected for their low expression of both Nore1A and Nore1B; the two NSCLC lines, A549 and NCI-H460, each have a mutant active Ras oncogene, whereas the two melanoma lines G361 and M14 each contain the constitutively active BRaf(V599E) oncogene and wild-type Ras. The expression of Nore1A or Nore1B suppresses colony formation by the A549 and G361 lines, as effectively in A549 as does RASSF1A; colony formation in the NCI-H460 and M14 lines is unaffected. Nore1A inhibits anchorage-independent growth by A549 cells and delays A549 progression through G1 without evidence of increased apoptosis. The growth suppressive action of Nore1A is largely unaffected by deletion of both the MST- and Ras-binding domains, as well as by mutation of the Nore1A zinc finger. Thus, Nore1 suppresses the growth of some tumor cell lines through as yet unidentified effectors, independent of Ras-like proteins or MST1/2.

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Acknowledgements

This work was supported by NIH Grants DK17776, CA073818 and institutional funds. We thank J Prendable for assistance in preparation of the manuscript.

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Authors and Affiliations

  1. Diabetes Unit and Medical Services, Massachusetts General Hospital, Boston, 02114, MA, USA

    Yumi Aoyama, Joseph Avruch & Xian-feng Zhang

  2. Department of Molecular Biology, Diabetes Research Laboratory, Massachusetts General Hospital, 50 Blossom Street, Boston, 02114, MA, USA

    Yumi Aoyama, Joseph Avruch & Xian-feng Zhang

  3. Department of Medicine, Harvard Medical School, Boston, 02114, MA, USA

    Yumi Aoyama, Joseph Avruch & Xian-feng Zhang

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  1. Yumi Aoyama
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Correspondence to Joseph Avruch or Xian-feng Zhang.

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Aoyama, Y., Avruch, J. & Zhang, Xf. Nore1 inhibits tumor cell growth independent of Ras or the MST1/2 kinases. Oncogene 23, 3426–3433 (2004). https://doi.org/10.1038/sj.onc.1207486

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