Unknown,Transcriptomics,Genomics,Proteomics

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IFN-alpha Stimulated Gene Expression in Sensitive and Resistant Renal Cell Carcinoma Cell Lines

ABSTRACT: The antiproliferative, antiviral, and immunomodulatory properties of interferons (IFNs) have led to its therapeutic implementation. IFNs effects are mediated by a complex network of signal transducers, culminating in IFN-stimulated gene (ISG) induction. This complexity leads to diverse clinical responses to IFN, from no response to complete regression of disease. Elucidation of ISG induction patterns is, therefore, essential to understand and maximize its therapeutic potential. To correlate ISG expression profiles with IFN responsiveness, two renal cell carcinoma (RCC) cell lines differing in antiviral and apoptotic response to IFN were treated with IFN-alpha for different times, and expression profiles were analyzed using a customized microarray containing 850 unique putative ISGs. Genes with similar kinetics of induction in both cell lines were clustered and analyzed for gene function. Seven sets of coordinately regulated genes were identified by k-means cluster analysis, and significant functional similarities were identified for five of the seven sets. Strikingly, expression of genes associated with transcription temporally preceded expression of those involved in signal transduction. Enhanced antiviral sensitivity to IFN was coincident with sustained expression of ISGs involved in transcriptional regulation. However, no difference in Stat1 activation was observed between the cell lines. Analysis of ISG expression patterns suggests that subtle differences in transcription profiles contribute to differences in IFN responsiveness. Two human renal cell carcinoma cell lines (ACHN and RCC1) were treated with IFN-alpha for 3, 6, 9, 12, 16, and 24 hours. Total RNA from treated cells (Cy5) is hybridized with total RNA from untreated control cells (Cy3) to the custom ISG 1.3.1 cDNA array.

ORGANISM(S): Homo sapiens

SUBMITTER: Bryan Williams

PROVIDER: E-GEOD-15193 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Functional annotation of IFN-alpha-stimulated gene expression profiles from sensitive and resistant renal cell carcinoma cell lines.

Holko Michelle M Williams Bryan R G BR Williams Bryan R G BR

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20060801 8

The antiproliferative, antiviral, and immunomodulatory properties of interferons (IFNs) have led to its therapeutic implementation. IFNs effects are mediated by a complex network of signal transducers, culminating in IFN-stimulated gene (ISG) induction. This complexity leads to diverse clinical responses to IFN, from no response to complete regression of disease. Elucidation of ISG induction patterns is, therefore, essential to understand and maximize its therapeutic potential. To correlate ISG ...[more]

PMID: 16881864

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Project description:Sensitivity to Interferon (IFN) is determined by a complex coordination of genetic and environmental factors. A previous experiment using two renal cancer cell lines differing markedly in their response to IFN were analyzed for their ISG profiles in order to determine gene expression changes associated with IFN sensitivity (Holko M, Williams BR. Functional annotation of IFN-alpha-stimulated gene expression profiles from sensitive and resistant renal cell carcinoma cell lines. J Interferon Cytokine Res 2006 Aug;26(8):534-47). Higher and more persistent expression of a subset of ISGs was noted in the IFN-sensitive RCC1 cells when compared with the relatively IFN-insensitive ACHN cells. A subset of Interferon stimulated genes (ISGs) whose sustained expression correlates with heightened IFN sensitivity were analyzed for functional and sequence similarities. This subset predominately contains genes involved in transcription, and most were found to contain in their promoters binding sites for promyleocytic zinc finger factor (PLZF), a transcriptional repressor identified by virtue of its role in the etiology of Acute Promyelocytic Leukemia (APL). Analysis of gene expression in a lymphoid cell line with inducible PLZF expression reveals that increased expression of immune system related genes including ISGs, depends on PLZF expression. Chromatin Immunoprecipitation assays show direct association between PLZF and in silico identified PLZF binding sites in ISG promoters. This study reveals a novel interaction between PLZF and IFN signaling. A time course of IFNa treatment (0, 6, 16, 24 hrs) was performed in tetetracycline induced PLZF overexpressing and control U937T:PLZF45 cells. For the 0 hr time point, PLZF overexpression (Cy5) was compared with control cells (Cy3). For the 6, 16, and 24 hr IFN treated time points, treated RNA was labelled with Cy5 and non-IFN treated RNA with Cy3. Each IFN treatment time point was performed on control and PLZF-overexpressing cells respectively.

Dataset Information

IFN-alpha Stimulated Gene Expression in Sensitive and Resistant Renal Cell Carcinoma Cell Lines

Publications

Functional annotation of IFN-alpha-stimulated gene expression profiles from sensitive and resistant renal cell carcinoma cell lines.

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