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

Luyang Sun, Lei Shi, Wenqian Li, Wenhua Yu, Jing Liang, Hua Zhang, Xiaohan Yang, Yan Wang, Ruifang Li, Xingrong Yao, Xia Yi, Yongfeng Shang

Research output: Contribution to journalArticle

42 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)10195-10200
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number25
DOIs
StatePublished - Jun 23 2009

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F-Box Proteins
Ligases
Ubiquitin
Maintenance
Forensic Anthropology
Ubiquitination
G1 Phase
Ionizing Radiation
Fingers
Cell Death
Cell Proliferation
Genome
Apoptosis
Kelch Repeat
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation. / Sun, Luyang; Shi, Lei; Li, Wenqian; Yu, Wenhua; Liang, Jing; Zhang, Hua; Yang, Xiaohan; Wang, Yan; Li, Ruifang; Yao, Xingrong; Yi, Xia; Shang, Yongfeng.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 25, 23.06.2009, p. 10195-10200.

Research output: Contribution to journalArticle

Sun, Luyang ; Shi, Lei ; Li, Wenqian ; Yu, Wenhua ; Liang, Jing ; Zhang, Hua ; Yang, Xiaohan ; Wang, Yan ; Li, Ruifang ; Yao, Xingrong ; Yi, Xia ; Shang, Yongfeng. / JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 25. pp. 10195-10200.
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