TY - JOUR
T1 - Dominant negative signal transducer and activator of transcription 2 (STAT2) protein
T2 - Stable expression blocks interferon α action in skin squamous cell carcinoma cells
AU - Clifford, John L.
AU - Yang, Xiulan
AU - Walch, Eugene
AU - Wang, Michael
AU - Lippman, Scott M.
PY - 2003/5
Y1 - 2003/5
N2 - We have demonstrated previously that suppression of some or all of the IFN-stimulated gene factor 3 (ISGF-3) proteins in skin squamous cell carcinomas is an early event in squamous skin carcinogenesis. This finding led to the hypothesis that suppressed expression of ISGF-3 proteins may lead to reduced IFN responsiveness, which in turn may contribute to skin malignancy by conferring a growth and/or survival advantage. To test this hypothesis, we have developed a skin cell-based model for inhibiting the IFN-α signaling pathway through the forced expression of a dominant negative-acting signal transducer and activator of transcription 2 (dnSTAT2) protein. Expression of dnSTAT2 suppressed cell growth inhibition with a pharmacologically achievable concentration (100 IU/ml) of IFN-α in the IFN-α-sensitive skin squamous cell carcinoma cell line SRB12-p9. dnSTAT2 also suppressed the IFN-α-induced phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT2, which are early events following IFN-α treatment, but did not suppress the IFN-γ-induced phosphorylation of STAT1. Finally, the dnSTAT2 protein suppressed the up-regulation of several IFN-α-inducible genes that were identified in this system by cDNA microarray screening. We conclude that the cell growth-inhibitory effect of IFN-α in skin cells requires an intact STAT2 protein and is therefore mediated by the ISGF-3 complex. These results support STAT2 as an important molecular target for skin cancer chemoprevention. Furthermore, we propose that these dnSTAT2-expressing cells provide a novel in vitro model for the study of type I IFN action in human skin cells.
AB - We have demonstrated previously that suppression of some or all of the IFN-stimulated gene factor 3 (ISGF-3) proteins in skin squamous cell carcinomas is an early event in squamous skin carcinogenesis. This finding led to the hypothesis that suppressed expression of ISGF-3 proteins may lead to reduced IFN responsiveness, which in turn may contribute to skin malignancy by conferring a growth and/or survival advantage. To test this hypothesis, we have developed a skin cell-based model for inhibiting the IFN-α signaling pathway through the forced expression of a dominant negative-acting signal transducer and activator of transcription 2 (dnSTAT2) protein. Expression of dnSTAT2 suppressed cell growth inhibition with a pharmacologically achievable concentration (100 IU/ml) of IFN-α in the IFN-α-sensitive skin squamous cell carcinoma cell line SRB12-p9. dnSTAT2 also suppressed the IFN-α-induced phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT2, which are early events following IFN-α treatment, but did not suppress the IFN-γ-induced phosphorylation of STAT1. Finally, the dnSTAT2 protein suppressed the up-regulation of several IFN-α-inducible genes that were identified in this system by cDNA microarray screening. We conclude that the cell growth-inhibitory effect of IFN-α in skin cells requires an intact STAT2 protein and is therefore mediated by the ISGF-3 complex. These results support STAT2 as an important molecular target for skin cancer chemoprevention. Furthermore, we propose that these dnSTAT2-expressing cells provide a novel in vitro model for the study of type I IFN action in human skin cells.
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M3 - Article
AN - SCOPUS:0141466300
SN - 1535-7163
VL - 2
SP - 453
EP - 459
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 5
ER -