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Involvement of p21 (waf1) in merlin deficient sporadic vestibular schwannomas.

Abstract
Previous studies have demonstrated that merlin acts as a tumor suppressor by blocking Ras-mediated signaling. However, the mechanism by which merlin controls cell proliferation has remained obscure. Here we show that merlin deficient tumors exhibited loss of p21, concomitant with elevated CDKs/cyclin D1 levels in sporadic vestibular schwannomas (VS) from clinic patients. Likewise, silencing of merlin gene expression in the cell lines resulted in down-regulation of p21. Furthermore, we find that merlin-enhanced p21 protein stability, rather than increased RNA accumulation, was responsible for the elevated p21 levels. Interestingly, p21 was required to maintain merlin levels and the inhibitory effect of merlin on Ras signaling was partially overridden by knockdown of p21. Consistent with the observation that over-expression of merlin arrested cell growth at G1-phase, the current study indicates that merlin exerts its antiproliferative effect, at least in part, by maintaining p21 expression, and loss of p21 is a prominent feature of merlin deficient schwannomas.
AuthorsH Wu, Y Chen, Z Y Wang, W Li, J Q Li, L Zhang, Y J Lu
JournalNeuroscience (Neuroscience) Vol. 170 Issue 1 Pg. 149-55 (Sep 29 2010) ISSN: 1873-7544 [Electronic] United States
PMID20600642 (Publication Type: Comparative Study, Journal Article)
CopyrightCopyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
Chemical References
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Neurofibromin 2
Topics
  • Animals
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21 (antagonists & inhibitors, deficiency, physiology)
  • Down-Regulation (genetics)
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Neurofibromin 2 (deficiency, genetics)
  • Neuroma, Acoustic (genetics, metabolism)
  • Tumor Cells, Cultured

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