Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation.

PLoS Pathog 2017 Jul 17;13(7):e1006517. Epub 2017 Jul 17.

The Wistar Institute, Program in Gene Expression and Regulation, Philadelphia, Pennsylvania, United States of America.

The chemical probe C60 efficiently triggers Epstein-Barr Virus (EBV) reactivation from latency through an unknown mechanism. Here, we identify the Cullin exchange factor CAND1 as a biochemical target of C60. We also identified CAND1 in an shRNA library screen for EBV lytic reactivation. Gene expression profiling revealed that C60 activates the p53 pathway and protein analysis revealed a strong stabilization and S15 phosphorylation of p53. C60 reduced Cullin1 association with CAND1 and led to a global accumulation of ubiquitylated substrates. C60 also stabilized the EBV immediate early protein ZTA through a Cullin-CAND1-interaction motif in the ZTA transcription activation domain. We propose that C60 perturbs the normal interaction and function of CAND1 with Cullins to promote the stabilization of substrates like ZTA and p53, leading to EBV reactivation from latency. Understanding the mechanism of action of C60 may provide new approaches for treatment of EBV associated tumors, as well as new tools to stabilize p53.

Download full-text PDF

Source
https://dx.plos.org/10.1371/journal.ppat.1006517
Publisher Site
http://dx.doi.org/10.1371/journal.ppat.1006517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531659PMC
July 2017
31 Reads

Publication Analysis

Top Keywords

epstein-barr virus
8
reactivation latency
8
triggers epstein-barr
8
ebv reactivation
8
c60
7
p53
5
ebv
5
reduced cullin1
4
stabilization s15
4
strong stabilization
4
revealed strong
4
p53 leading
4
zta p53
4
s15 phosphorylation
4
p53 c60
4
substrates zta
4
stabilization substrates
4
analysis revealed
4
phosphorylation p53
4
c60 reduced
4

References

(Supplied by CrossRef)
Epstein-Barr virus: 40 years on
LS Young et al.
Nature reviews Cancer 2004
Epstein-Barr virus: more than 50 years old and still providing surprises
LS Young et al.
Nat Rev Cancer 2016
Woodward Award: development of novel, EBV-targeted therapies for EBV-positive tumors
S Kenney et al.
Transactions of the American Clinical and Climatological Association 2006
Adoptive T-Cell Immunotherapy
S Gottschalk et al.
Curr Top Microbiol Immunol 2015
Epstein-Barr Virus Lytic Cycle Reactivation
J McKenzie et al.
Curr Top Microbiol Immunol 2015

Similar Publications