TY - JOUR
T1 - Elevated expression of ISG15 in tumor cells interferes with the ubiquitin/26S proteasome pathway
AU - Desai, Shyamal D.
AU - Haas, Arthur L.
AU - Wood, Laurence M.
AU - Tsai, Yu Chen
AU - Pestka, Sidney
AU - Rubin, Eric H.
AU - Saleem, Ahamed
AU - Nur-E-Kamal, Alam
AU - Liu, Leroy F.
PY - 2006/1/15
Y1 - 2006/1/15
N2 - IFN-stimulatory gene factor 15 (ISG15) is a ubiquitin-like protein, which is conjugated to many cellular proteins. However, its role in protein degradation is unclear. Here, we show that ISG15 is highly elevated and extensively conjugated to cellular proteins in many tumors and tumor cell lines. The increased levels of ISG15 in tumor cells were found to be associated with decreased levels of polyubiquitinated proteins. Specific knockdown of ISG15 expression using ISG15-specific small interfering RNA (siRNA) was shown to increase the levels of polyubiquitinated proteins, suggesting an antagonistic role of ISG15 in regulating ubiquitin-mediated protein turnover. Moreover, siRNA-mediated down-regulation of the major E2 for ISG15 (UbcH8), which blocked the formation of ISG15 protein conjugates, also increased the levels of polyubiquitinated proteins. Together, our results suggest that the ISG15 pathway, which is deregulated during tumorigenesis, negatively regulates the ubiquitin/proteasome pathway by interfering with protein polyubiquitination/ degradation.
AB - IFN-stimulatory gene factor 15 (ISG15) is a ubiquitin-like protein, which is conjugated to many cellular proteins. However, its role in protein degradation is unclear. Here, we show that ISG15 is highly elevated and extensively conjugated to cellular proteins in many tumors and tumor cell lines. The increased levels of ISG15 in tumor cells were found to be associated with decreased levels of polyubiquitinated proteins. Specific knockdown of ISG15 expression using ISG15-specific small interfering RNA (siRNA) was shown to increase the levels of polyubiquitinated proteins, suggesting an antagonistic role of ISG15 in regulating ubiquitin-mediated protein turnover. Moreover, siRNA-mediated down-regulation of the major E2 for ISG15 (UbcH8), which blocked the formation of ISG15 protein conjugates, also increased the levels of polyubiquitinated proteins. Together, our results suggest that the ISG15 pathway, which is deregulated during tumorigenesis, negatively regulates the ubiquitin/proteasome pathway by interfering with protein polyubiquitination/ degradation.
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UR - http://www.scopus.com/inward/citedby.url?scp=31544460359&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-05-1123
DO - 10.1158/0008-5472.CAN-05-1123
M3 - Article
C2 - 16424026
AN - SCOPUS:31544460359
SN - 0008-5472
VL - 66
SP - 921
EP - 928
JO - Cancer Research
JF - Cancer Research
IS - 2
ER -
