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First published online 10 February 2009
doi: 10.1242/jcs.037556

Journal of Cell Science 122, 595-599 (2009)
Published by The Company of Biologists 2009
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Short Report

Expression of the proneural gene encoding Mash1 suppresses MYCN mitotic activity

Rubén Álvarez-Rodríguez and Sebastián Pons*

Department of Cell Death and Proliferation, Institute for Biomedical Research of Barcelona, IIBB-CSIC-IDIBAPS, Barcelona, Spain

* Author for correspondence (e-mail: spfnqi{at}iibb.csic.es)

Accepted 10 November 2008

Summary

Murine Mash1 (Ascl1) is a member of the basic helix-loop-helix family of transcription factors and has been described to promote differentiation in some neural precursors. The process of differentiation is coordinated with a concomitant cell-cycle arrest, but the molecular mechanism of this process is unclear. Here, we describe for the very first time a direct regulation of an oncogene by a proneural gene. When expressed in proliferating cerebellar granular precursors, expression of the proneural gene encoding Mash1 promotes cell-cycle exit and differentiation, whereas expression of the oncogene MYCN has the opposite effect, promoting the proliferation of these cells in the absence of sonic hedgehog. Moreover, Mash1 overexpression neutralizes MYCN-induced proliferation. We now propose that the mechanism of antagonism between both molecules is based on opposite functions in the transcriptional regulation of the E-box motif, particularly in the E-boxes within the cyclin-D2 promoter, with MYCN acting as a transcriptional activator and Mash1 as a repressor. In agreement with this result, overexpression of cyclin D2 suppressed the anti-proliferative activity of Mash1.

Key words: MYCN, Mash1, Cyclin D2, Proneural, Oncogene, Cerebellar granular neuronal precursors


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