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Identification and functional characterization of FMN2, a regulator of the cyclin-dependent kinase inhibitor p21.

Abstract
The ARF tumor suppressor is a central component of the cellular defense against oncogene activation in mammals. p14ARF activates p53 by binding and inhibiting HDM2, resulting, inter alia, in increased transcription and expression of the cyclin-dependent kinase inhibitor p21 and consequent cell-cycle arrest. We analyzed the effect of p14ARF induction on nucleolar protein dynamics using SILAC mass spectrometry and have identified the human Formin-2 (FMN2) protein as a component of the p14ARF tumor suppressor pathway. We show that FMN2 is increased upon p14ARF induction at both the mRNA and the protein level via a NF-κB-dependent mechanism that is independent of p53. FMN2 enhances expression of the cell-cycle inhibitor p21 by preventing its degradation. FMN2 is also induced by activation of other oncogenes, hypoxia, and DNA damage. These results identify FMN2 as a crucial component in the regulation of p21 and consequent oncogene/stress-induced cell-cycle arrest in human cells.
AuthorsKayo Yamada, Motoharu Ono, Neil D Perkins, Sonia Rocha, Angus I Lamond
JournalMolecular cell (Mol Cell) Vol. 49 Issue 5 Pg. 922-33 (Mar 07 2013) ISSN: 1097-4164 [Electronic] United States
PMID23375502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Inc. All rights reserved.
Chemical References
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • NF-kappa B
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Tumor Suppressor Protein p14ARF
Topics
  • Cell Cycle Checkpoints
  • Cell Cycle Proteins (genetics, metabolism)
  • Cell Line, Tumor
  • Cell Nucleolus
  • Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
  • Humans
  • Mass Spectrometry
  • NF-kappa B (genetics)
  • Nerve Tissue Proteins (genetics, metabolism)
  • Proteomics
  • RNA, Messenger (metabolism)
  • Tumor Suppressor Protein p14ARF (genetics, metabolism)

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