USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1

• Published in: The EMBO journal Vol. 30; no. 11; pp. 2177 - 2189
• Main Authors: Zhang, Xinna, Berger, Franklin G, Yang, Jianhua, Lu, Xiongbin
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.06.2011; Nature Publishing Group UK; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Animals; Apoptosis; ARF-BP1; Cells, Cultured; Deoxyribonucleic acid; deubiquitination; DNA; DNA damage; EMBO13; EMBO31; Fibroblasts - physiology; Gene Knockout Techniques; Genomes; Ionizing radiation; Mice; Mice, Knockout; Molecular biology; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; p53; Peptides; Proteins; Proto-Oncogene Proteins; Radiation, Ionizing; Radiography; Spleen - pathology; Spleen - radiation effects; Thymus Gland - diagnostic imaging; Thymus Gland - pathology; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Proteins; Tumors; Ubiquitin Thiolesterase; Ubiquitin-Protein Ligases - metabolism; Ubiquitin-Specific Proteases; USP4; ARF‐BP1; deubiquitination; USP4; p53
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2011.125

Tumour suppressor p53 levels in the cell are tightly regulated by controlled degradation through ubiquitin ligases including Mdm2, COP1, Pirh2, and ARF‐BP1. The ubiquitination process is reversible via deubiquitinating enzymes, such as ubiquitin‐specific peptidases (USPs). In this study, we identified ubiquitin‐specific peptidase 4 (USP4) as an important regulator of p53. USP4 interacts directly with and deubiquitinates ARF‐BP1, leading to the stabilization of ARF‐BP1 and subsequent reduction of p53 levels. Usp4 knockout mice are viable and developmentally normal, but showed enhanced apoptosis in thymus and spleen in response to ionizing radiation. Compared with wild‐type mouse embryonic fibroblasts (MEFs), Usp4 −/− MEFs exhibited retarded growth, premature cellular senescence, resistance to oncogenic transformation, and hyperactive DNA damage checkpoints, consistent with upregulated levels and activity of p53 in the absence of USP4. Finally, we showed that USP4 is overexpressed in several types of human cancer, suggesting that USP4 is a potential oncogene. Another DUB joins the ranks of deubiquitinating enzymes involved in p53 regulation. USP4 acts on the ubiquitin ligase ARF‐BP1/Mule/Huwe1, thus decreasing p53 levels and responses; while senescence ensues in USP4‐deficient cells.