The APC/C and CBP/p300 cooperate to regulate transcription and cell-cycle progression.
The anaphase-promoting complex/cyclosome (APC/C) is a multicomponent E3 ubiquitin ligase that, by targeting protein substrates for 26S proteasome-mediated degradation through ubiquitination, coordinates the temporal progression of eukaryotic cells through mitosis and the subsequent G1 phase of the cell cycle. Other functions of the APC/C are, however, less well defined. Here we show that two APC/C components, APC5 and APC7, interact directly with the coactivators CBP and p300 through protein-protein interaction domains that are evolutionarily conserved in adenovirus E1A. This interaction stimulates intrinsic CBP/p300 acetyltransferase activity and potentiates CBP/p300-dependent transcription. We also show that APC5 and APC7 suppress E1A-mediated transformation in a CBP/p300-dependent manner, indicating that these components of the APC/C may be targeted during cellular transformation. Furthermore, we establish that CBP is required in APC/C function; specifically, gene ablation of CBP by RNA-mediated interference markedly reduces the E3 ubiquitin ligase activity of the APC/C and the progression of cells through mitosis. Taken together, our results define discrete roles for the APC/C-CBP/p300 complexes in growth regulation.
Turnell
Andrew S
AS
Cancer Research UK Institute for Cancer Studies, The Medical School, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. A.S.Turnell@bham.ac.uk
Stewart
Grant S
GS
Grand
Roger J A
RJ
Rookes
Susan M
SM
Martin
Ashley
A
Yamano
Hiroyuki
H
Elledge
Stephen J
SJ
Gallimore
Phillip H
PH
D017500:Adenovirus E1A Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D064193:Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome; D064195:Apc7 Subunit, Anaphase-Promoting Complex-Cyclosome; D050882:CREB-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D017124:Conserved Sequence; D005786:Gene Expression Regulation; D006801:Humans; D008938:Mitosis; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic; D043743:Ubiquitin-Protein Ligase Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C577375:ANAPC5 protein, human; C577399:ANAPC7 protein, human; D017500:Adenovirus E1A Proteins; D064193:Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome; D064195:Apc7 Subunit, Anaphase-Promoting Complex-Cyclosome; D050882:CREB-Binding Protein; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome