TY - JOUR
T1 - JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation
AU - Sun, Luyang
AU - Shi, Lei
AU - Li, Wenqian
AU - Yu, Wenhua
AU - Liang, Jing
AU - Zhang, Hua
AU - Yang, Xiaohan
AU - Wang, Yan
AU - Li, Ruifang
AU - Yao, Xingrong
AU - Yi, Xia
AU - Shang, Yongfeng
PY - 2009/6/23
Y1 - 2009/6/23
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.0901864106
DO - 10.1073/pnas.0901864106
M3 - Article
C2 - 19509332
AN - SCOPUS:67649852552
SN - 0027-8424
VL - 106
SP - 10195
EP - 10200
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 25
ER -