Journal
MOLECULAR CELL
Volume 49, Issue 5, Pages 922-933Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2012.12.023
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Funding
- Wellcome Trust [083524/Z/07/Z, 073980/Z/03/Z, 08136/Z/03/Z, 0909444/Z/09/Z]
- MRC Milstein Award [G0801738]
- BBSRC RASOR (Radical Solutions for Researching the Proteome) network
- EU FP7 Prospects Network [HEALTH-F4-2008-201648]
- Cancer Research UK Senior Research Fellow [C9667/A12918]
- Cancer Research UK [C1443/A12750]
- MRC [G0801738] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/C511613/1] Funding Source: researchfish
- Cancer Research UK [12750, 12918] Funding Source: researchfish
- Medical Research Council [G0801738] Funding Source: researchfish
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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-kappa B-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.
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