Title

CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53

UMMS Affiliation

Department of Cancer Biology; Department of Medicine, Division of Hematology/Oncology

Date

10-7-2009

Document Type

Article

Subjects

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

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: 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

Related Resources

Link to Article in PubMed

Journal Title

Proceedings of the National Academy of Sciences of the United States of America [corrected to Kung, Andrew L]

PubMed ID

19805293