COP9 subunits 4 and 5 target soluble guanylyl cyclase α1 and p53 in prostate cancer cells.
Our laboratory previously has identified soluble guanylyl cyclase α1 (sGCα1) as a direct target of androgen receptor and essential for prostate cancer cell growth via a pathway independent of nitric oxide (NO) signaling. We identified the COP9 signalosome subunit 4 (CSN4) as a novel interacting partner for sGCα1. Importantly, the CSN4-sGCα1 interaction inhibits sGCα1 proteasomal degradation. Consistent with this, disruption of CSN4 led to a significant decrease in prostate cancer cell proliferation, which was significantly but not completely rescued by sGCα1 overexpression, opening the possibility of an additional target of CSN4. Interestingly, immunoprecipitation experiments showed that p53 is found in the CSN4-sGCα1 cytoplasmic protein complex. However, in contrast to sGCα1, p53 protein stability was compromised by CSN4, leading to prostate cancer cell survival and proliferation. Interestingly, we observed that CSN4 was overexpressed in prostate tumors, and its protein level correlates directly with sGCα1 and inversely with p53 proteins, mimicking what was observed in prostate cancer cells. Our data further showed that CSN4 silencing decreased CSN5 protein levels and suggest that the CSN4 effects on sGCα1 and p53 proteins are mediated by CSN5. Lastly, our study showed that caseine kinase-2 (CK2) was involved in regulating p53 and sGCα1 protein stability as determined by both disruption of CK2 expression and inhibition of its kinase activity. Collectively, our study has identified a novel endogenous CSN4-CSN5-CK2 complex with sGCα1and p53 that oppositely controls the stability of these 2 proteins and provides prostate cancer cells an important mechanism for survival and proliferation.
Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606.
Meenakshi
M
Bhansali
Lirim
L
Shemshedini
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000075686:COP9 Signalosome Complex; D047390:Casein Kinase II / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004795:Enzyme Stability; D015972:Gene Expression Regulation, Neoplastic; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D010447:Peptide Hydrolases / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000201:enzymology*; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C555813:COPS4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D047390:Casein Kinase II; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase