Elevated expression of ISG15 in tumor cells interferes with the ubiquitin/26S proteasome pathway

Shyamal D. Desai, Arthur L. Haas, Laurence M. Wood, Yu Chen Tsai, Sidney Pestka, Eric H. Rubin, Ahamed Saleem, Alam Nur-E-Kamal, Leroy-Fong Liu

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)921-928
Number of pages8
JournalCancer Research
Volume66
Issue number2
DOIs
Publication statusPublished - Jan 15 2006
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Desai, S. D., Haas, A. L., Wood, L. M., Tsai, Y. C., Pestka, S., Rubin, E. H., Saleem, A., Nur-E-Kamal, A., & Liu, L-F. (2006). Elevated expression of ISG15 in tumor cells interferes with the ubiquitin/26S proteasome pathway. Cancer Research, 66(2), 921-928. https://doi.org/10.1158/0008-5472.CAN-05-1123