title: JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation.
abstract: 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 G(1) 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, China.
authors.forename: Luyang
authors.initials: L
authors.lastname: Sun
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Wenqian
authors.initials: W
authors.lastname: Li
authors.forename: Wenhua
authors.initials: W
authors.lastname: Yu
authors.forename: Jing
authors.initials: J
authors.lastname: Liang
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Ruifang
authors.initials: R
authors.lastname: Li
authors.forename: Xingrong
authors.initials: X
authors.lastname: Yao
authors.forename: Xia
authors.initials: X
authors.lastname: Yi
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Shang
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017434:Protein Structure, Tertiary; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D044783:F-Box Proteins; C542109:FBXO42 protein, human; C479529:RBX1 protein, human; D016159:Tumor Suppressor Protein p53; D044843:SKP Cullin F-Box Protein Ligases