Abstract
The cellular level of the tumor suppressor p53 is tightly regulated through induced degradation via the ubiquitin/proteasome system. The ubiquitin ligase Mdm2 plays a pivotal role in stimulating p53 turnover. However, recently additional ubiquitin ligases have been identified that participate in the degradation of the tumor suppressor. Apparently, multiple degradation pathways are employed to ensure proper destruction of p53. Here we show that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53. CHIP-induced degradation was observed for mutant p53, which was previously shown to associate with the chaperones Hsc70 and Hsp90, and for the wild-type form of the tumor suppressor. Our data reveal that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association.
Highlights
The cellular level of the tumor suppressor p53 is tightly regulated through induced degradation via the ubiquitin/proteasome system
Despite the central role of Mdm2 in proteasomal targeting of p53, additional ubiquitin ligases were recently shown to participate in the degradation of the tumor suppressor in normal cells, including p300, Pirh2, and COP1 [21,22,23]
We identify a novel degradation pathway for the tumor suppressor p53. This pathway is entered through a transient association of wild-type and mutant p53 with molecular chaperones and involves the chaperone-associated ubiquitin ligase CHIP
Summary
E3, ubiquitin-protein isopeptide ligase; E2, ubiquitin carrier protein; E1, ubiquitin-activating enzyme; MOPS, 3-(N-morpholino)propanesulfonic acid; siRNA, small interfering RNA; GA, geldanamycin. Mdm2-mediated ubiquitylation targets p53 for degradation by the 26 S proteasome and is of central importance for establishing low p53 levels in normal cells [13, 14]. Despite the central role of Mdm in proteasomal targeting of p53, additional ubiquitin ligases were recently shown to participate in the degradation of the tumor suppressor in normal cells, including p300, Pirh, and COP1 [21,22,23]. Wild-type p53 possesses an intrinsic conformational lability [48, 49], and may undergo dynamic associations with molecular chaperones at a posttranslational stage Such associations may modulate the presentation of p53 for degradation and could serve as sensors of cell stress. We show that wild-type p53 and an Arg175 mutant form of the tumor suppressor (p53R175H) can be targeted for proteasomal degradation by the CHIP ubiquitin ligase. Our data reveal a novel degradation pathway for the tumor suppressor that is entered through a transient association of wild-type and mutant p53 with molecular chaperones
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
