JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation.
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.
Sun
Luyang
L
Department of Biochemistry and Molecular Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, China.
Shi
Lei
L
Li
Wenqian
W
Yu
Wenhua
W
Liang
Jing
J
Zhang
Hua
H
Yang
Xiaohan
X
Wang
Yan
Y
Li
Ruifang
R
Yao
Xingrong
X
Yi
Xia
X
Shang
Yongfeng
Y
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
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