Identification and Functional Characterization of FMN2, a Regulator of the Cyclin-Dependent Kinase Inhibitor p21

Kayo Yamada,Motoharu Ono,Neil D Perkins,Sonia Rocha,Angus I Lamond

doi:10.1016/j.molcel.2012.12.023

Abstract

SummaryThe 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.

Highlights

The ARF tumor suppressor initiates the cellular response to aberrant oncogene activation through binding to and inhibiting the activity of Hdm2/Mdm2, the E3 ubiquitin ligase for p53 (Sherr, 2001; Vousden, 2002)
The results demonstrate that FMN2 is required for p21 protein expression, following ARF induction and following hypoxia and etoposide-induced DNA damage (Figure 6B), indicating a more general role for FMN2 in the control of p21 protein levels
FMN2 Is Induced Following ARF Induction, Oncogenic Stress, DNA Damage, and Hypoxia In this study we have identified FMN2 as a key human protein involved in stress-induced cell-cycle arrest

Summary

Introduction

The ARF tumor suppressor initiates the cellular response to aberrant oncogene activation through binding to and inhibiting the activity of Hdm2/Mdm, the E3 ubiquitin ligase for p53 (Sherr, 2001; Vousden, 2002). Upon ARF induction, p53 can escape from degradation and activate transcription of its target genes. These include proapoptotic genes such as puma and noxa (Zilfou and Lowe, 2009) and cell-cycle inhibitors such as p21 (Zilfou and Lowe, 2009). A high percentage of human leukemia and melanoma patients have ARF mutations (Curtin et al, 2005; Goldstein et al, 2007; Soufir et al, 2004). Genetic studies have shown that ARF deletion promotes tumor development with high frequency (Sherr, 2001). Genetic and biochemical studies on p53 and ARF pathways showed there are ARF tumor suppressor pathways that are p53 independent (Chen et al, 2009; Rocha et al, 2003, 2005; Wadhwa et al, 2002; Weber et al, 2000)

Results

Discussion

Conclusion