JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-06, Vol.106 (25), p.10195-10200
• Main Authors: Sun, Luyang, Shi, Lei, Li, Wenqian, Yu, Wenhua, Liang, Jing, Zhang, Hua, Yang, Xiaohan, Wang, Yan, Li, Ruifang, Yao, Xingrong, Yi, Xia, Shang, Yongfeng
• Format: Article
• Language: English
• Subjects: Apoptosis; Biological Sciences; Carrier Proteins - metabolism; Cell cycle; Cell cycle proteins; Cell Line, Tumor; Cells; Cullin Proteins - metabolism; Enzyme kinetics; F box proteins; F-Box Proteins - genetics; F-Box Proteins - metabolism; Gene expression regulation; Genomics; Humans; Immunoblotting; Messenger RNA; Protein Structure, Tertiary; Proteins; SKP Cullin F-Box Protein Ligases - metabolism; Small interfering RNA; Tumor Suppressor Protein p53 - metabolism; Tumors; Two-Hybrid System Techniques; Ubiquitination; Ubiquitins; Western blotting
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0901864106

The p53 tumor suppressor plays a central role in integrating cellular responses to various stresses. Tight regulation of p53 is thus essential for the maintenance of genome integrity and normal cell proliferation. Currently, several ubiquitin ligases, including the single-subunit RING-finger types--MDM2, Pirh2, and COP1--and the HECT-domain type--ARF-BP1--have been reported to target p53 for degradation. Here, we report the identification of a human Kelch domain-containing F-box protein, JFK. We showed that JFK promotes ubiquitination and degradation of p53. But unlike MDM2, Pirh2, COP1, and ARF-BP1, all of which possess an intrinsic ubiquitin ligase activity, JFK destabilizes p53 through the assembly of a Skp1-Cul1-F-box complex. Significantly, JFK inhibits p53-dependent transcription, and depletion of JFK stabilizes p53, promotes cell apoptosis, arrests cells in the G₁ phase, and sensitizes cells to ionizing radiation-induced cell death. These data indicate that JFK is a critical negative regulator of p53 and represents a pathway for the maintenance of p53 levels in unstressed cells. Our experiments link the Skp1-Cul1-F-box system to p53 regulation.