CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53
Department of Cancer Biology; Department of Medicine, Division of Hematology/Oncology
CREB-Binding Protein; Cell Line, Tumor; Cytoplasm; E1A-Associated p300 Protein; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Polyubiquitin; Reverse Transcriptase Polymerase Chain Reaction; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Ubiquitin-Protein Ligase Complexes; Ubiquitin-Protein Ligases
Life Sciences | Medicine and Health Sciences
p300 and CREB-binding protein (CBP) act as multifunctional regulators of p53 via acetylase and polyubiquitin ligase (E4) activities. Prior work in vitro has shown that the N-terminal 595 aa of p300 encode both generic ubiquitin ligase (E3) and p53-directed E4 functions. Analysis of p300 or CBP-deficient cells revealed that both coactivators were required for endogenous p53 polyubiquitination and the normally rapid turnover of p53 in unstressed cells. Unexpectedly, p300/CBP ubiquitin ligase activities were absent in nuclear extracts and exclusively cytoplasmic. Consistent with the cytoplasmic localization of its E3/E4 activity, CBP deficiency specifically stabilized cytoplasmic, but not nuclear p53. The N-terminal 616 aa of CBP, which includes the conserved Zn(2+)-binding C/H1-TAZ1 domain, was the minimal domain sufficient to destabilize p53 in vivo, and it included within an intrinsic E3 autoubiquitination activity and, in a two-step E4 assay, exhibited robust E4 activity for p53. Cytoplasmic compartmentalization of p300/CBP's ubiquitination function reconciles seemingly opposed functions and explains how a futile cycle is avoided-cytoplasmic p300/CBP E4 activities ubiquitinate and destabilize p53, while physically separate nuclear p300/CBP activities, such as p53 acetylation, activate p53.
DOI of Published Version
Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16275-80. Epub 2009 Sep 4. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America [corrected to Kung, Andrew L]
Shi, Dingding; Pop, Marius S.; Kulikov, Roman; Love, Ian M.; Kung, Andrew L.; and Grossman, Steven R., "CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53" (2009). Open Access Articles. 2202.