Involvement of PML nuclear bodies in CBP degradation through the ubiquitin-proteasome pathway.
Transcriptional coactivator CBP is involved in the regulation of an array of biological processes including cellular differentiation, proliferation and survival. The function of CBP is critical for proper embryonic development and is relevant in cancer biology. Although much is known about the functional roles of CBP in these cellular processes, fewer studies have assessed what in turn regulates CBP activity per se. It has been reported that CBP colocalizes with PML bodies which are nuclear structures disrupted in acute promyelocytic leukemia. However, the biological relevance of CBP localization to PML nuclear bodies is still unclear. In this study, we demonstrate that histone deacetylase inhibitors such as valproic acid, a therapeutically relevant compound used for the treatment of epilepsy, modulates CBP activity. Valproic acid reduces the steady-state level of CBP by inducing CBP degradation through the ubiquitin-proteasome pathway, while increasing the colocalization of CBP with ubiquitin nuclear speckles and with PML nuclear bodies. Our results suggest that PML nuclear bodies are nuclear sites involved in the ubiquitin-dependent degradation of CBP, providing novel insights in the regulation of CBP function and highlighting the relevance of its localization to PML nuclear bodies.
St-Germain
Jonathan R
JR
Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Chen
Jihong
J
Li
Qiao
Q
D050882:CREB-Binding Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000187:drug effects / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology
D025801:Ubiquitin; D014635:Valproic Acid; D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein; D046988:Proteasome Endopeptidase Complex