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. Previously, we reported that JFK, the only Kelch domain-containing F-box protein in human, promotes ubiquitination and degradation of p53 and that unlike the other E3 ligases for p53, all of which possess an intrinsic ubiquitin ligase activity, JFK destabilizes p53 through the assembly of a Skp1-Cul1-F-box complex. Here, we report that the substrate recognition by JFK requires phosphorylation of p53 in its central core region by CSN (COP9 signalosome)-associated kinase. Significantly, inhibition of CSN-associated kinase activity or knockdown of CSN5 impairs JFK-promoted p53 degradation, enhances p53-dependent transcription, and promotes cell growth suppression, G(1) arrest, and apoptosis. Moreover, we showed that JFK is transcriptionally regulated by p53 and forms an auto-regulatory negative feedback loop with p53. These data may shed new light on the functional connection between CSN, Skp1-Cul1-F-box ubiquitin ligase, and p53 and provide a molecular mechanism for the regulation of JFK-promoted p53 degradation.
Highlights
Mechanisms, including cell cycle arrest, apoptosis, and cellular senescence [2, 6]
Phosphorylation of p53 by CSN-associated Kinase Is Required for Substrate Recognition by JFK—Previously, we showed that JFK promotes p53 degradation through the formation of an SCF complex in which JFK serves as a substrate receptor [11]
Current literature indicates that p53 degradation is executed by several ubiquitin ligases, including MDM2, Pirh2, COP1, and ARF-BP1, and is ensured by auto-regulatory negative feedback loops between p53 and each of MDM2, Pirh2, and COP1
Summary
Mechanisms, including cell cycle arrest, apoptosis, and cellular senescence [2, 6]. As inactivation or activation of p53 sets up life or death decisions, an exquisite mechanism has evolved to control its erroneous activation at the same time as initiating prompt stress responses. The result suggests that the CSN-associated kinase function is required for p53 recognition by JFK and further supports a phosphorylation-dependent interaction of p53 with JFK.
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