Bone morphogenetic protein 2 opposes Shh-mediated proliferation in cerebellar granule cells through a TIEG-1-based regulation of Nmyc.

Published

Journal Article

Nmyc is a potent regulator of cell cycle in cerebellar granular neuron precursors (CGNPs) and has been proposed to be the main effector of Shh (Sonic hedgehog) proliferative activity. Nmyc ectopic expression is sufficient to promote cell autonomous proliferation and can lead to tumorigenesis. Bone morphogenetic protein 2 (BMP2) antagonizes Shh proliferative effect by promoting cell cycle exit and differentiation in CGNPs. Here we report that BMP2 opposes Shh mitogenic activity by blocking Nmyc expression. We have identified TIEG-1 (KLF10) as the intermediary factor that blocks Nmyc expression through the occupancy of the Sp1 sites present in its promoter. We also demonstrate that TIEG-1 ectopic expression in CGNPs induces cell cycle arrest that can lead to apoptosis but fails to promote differentiation. Moreover, TIEG-1 synergizes with BMP2 activity to terminally differentiate CGNPs and independent differentiator signals such as dibutyryl cAMP and prevents apoptosis in TIEG-1 arrested cells. All together, these data strongly suggest that the BMP2 pathway triggers cell cycle exit and differentiation as two separated but coordinated processes, where TIEG-1 acts as a mediator of the cell cycle arrest.

Full Text

Duke Authors

Cited Authors

  • Alvarez-Rodríguez, R; Barzi, M; Berenguer, J; Pons, S

Published Date

  • December 21, 2007

Published In

Volume / Issue

  • 282 / 51

Start / End Page

  • 37170 - 37180

PubMed ID

  • 17951258

Pubmed Central ID

  • 17951258

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M705414200

Language

  • eng

Conference Location

  • United States