Roles for CSN5 in control of p53/MDM2 activities.
The 5th subunit of COP9 signalosome (CSN5, also known as Jab1 or COPS5) is implicated in regulating p53 activity and is overexpressed in various tumors. However, the precise roles of CSN5 in p53 network and tumorigenesis are not well characterized. Here we show that CSN5 is a critical regulator of both p53 and MDM2. We show that curcumin, an important inhibitor of CSN-associated kinases, can downregulate not only CSN5 but also MDM2, which results in p53 stabilization. Importantly, CSN5 interacts with p53. CSN5 expression leads to p53 degradation, facilitating MDM2-mediated p53 ubiquitination, and promoting p53 nuclear export. Additionally, CSN5 expression results in stabilization of MDM2 through reducing MDM2 self-ubiquitination and decelerating turnover rate of MDM2. Significantly, we further show that CSN5 antagonizes the transcriptional activity of p53. These results demonstrate that CSN5 is a pivotal regulator for both p53 and MDM2. Our studies may pave the way for targeting CSN5 for anti-cancer drug development.
Zhang
Xiao-Chun
XC
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Chen
Jian
J
Su
Chun-Hui
CH
Yang
Heng-Yin
HY
Lee
Mong-Hong
MH
D021581:Active Transport, Cell Nucleus; D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D010447:Peptide Hydrolases / Q000502:physiology*; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D003474:Curcumin