Abstracts (complete list) - Wissenschaft Online

Andrea Kiessling, Dagmar Riemann, Susanne Fuessel, Esther Kamphausen, Barbara
Seliger
Characterization of expression pattern and regulation of
ISGylation system in tumors
Following the identification of ubiquitin as central regulator of proteasomal degradation,
a number of ubiquitin-like proteins have been identified. Interferon-stimulated gene 15
(ISG15), a member of this family, was recently described to exert a dual function as
intracellular modifier of proteins negatively regulating the polyubiquitination and as an
extracellular cytokine-like modulator of innate immune responses.
In this study, we analyzed the expression and regulation of ISG15 and of the enzymes
involved in ISG15 conjugation to proteins (Ube1L, UbcH8, and Herc5) in human tumors.
By quantitative PCR, all components of the ISGylation system were found in 16/17 renal
cell carcinoma (RCC), 6/7 squamous cell carcinoma, 37/39 melanoma, and 2/2 prostate
carcinoma cell lines. However, basal expression levels of the individual components did
not strictly correlate with each other. The transcript quantification in paired malignant
and non-malignant tissue samples from RCC patients revealed increased ISG15 and
UbcH8 expression in the tumors in 9/9 and 6/9 tissue samples, respectively. In
contrast, Ube1L and Herc5 were heterogeneously expressed in the tumors. In paired
specimens from prostate cancer patients, ISG15 and UbcH8 were upregulated in 11/14
tumors and 10/14 tumors, respectively. Furthermore, the tumor-associated expression
of these genes was more prominent in advanced tumors.
In order to determine the functional role of ISG15 in tumors, the regulation of
ISGylation system by various stimuli was analyzed. The ISGylation system was highly
upregulated by type I IFN in tumor cell lines of distinct origin and by type II IFN
particularly in melanoma cell lines. According to the presence of several p53 sites in the
ISG15 promoter, ISG15, but none of the other ISGylation components, was increased
after exposure to UV light.
Our results show that ISG15, in contrast to the other components of ISGylation, is
upregulated in tumors, indicating (i) an IFN-independent, cell stress-mediated
mechanism of regulation, and (ii) a role of ISG15 in tumors that is independent from its
function as covalent modifier of proteins.