Identification of genes differentially regulated by interferon α, β, or γ using oligonucleotide arrays

Der, Sandy D.; Zhou, Aimin; Williams, Bryan R.G.; Silverman, Robert H.

doi:10.1073/pnas.95.26.15623

Cited by 1,670 publications

(1,316 citation statements)

References 28 publications

Supporting

Mentioning

1,243

Contrasting

Unclassified

Order By: Relevance

“…Type I IFNs bind to the IFN-α receptor 1 (IFNAR1) and IFNAR2 polypeptide chains on cell surfaces initiating JAK-STAT signaling to the IFN stimulated genes (ISGs) [1]. Included among over a hundred different ISGs are genes encoding 2-5A synthetases (OAS) [2,3]. The OAS genes are a family of ISGs that function in the 2-5A/RNase L system (Fig.…”

Section: Background On the 2-5a/rnase L Systemmentioning

confidence: 99%

A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

Self Cite

View full text Add to dashboard Cite

The antiviral and antitumor actions of interferons are caused, in part, by a remarkable regulated RNA cleavage pathway known as the 2-5A/RNase L system. 2′-5′ linked oligoadenylates (2-5A) are produced from ATP by interferon-inducible synthetases. 2-5A activates pre-existing RNase L, resulting in the cleavage of RNAs within single-stranded regions. Activation of RNase L by 2-5A leads to an antiviral response, although precisely how this happens is a subject of ongoing investigations. Recently, RNase L was identified as the hereditary prostate cancer 1 gene. That finding has led to the discovery of a novel human retrovirus, XMRV. My scientific journey through the 2-5A system recounts some of the highlights of these efforts. Knowledge gained from studies on the 2-5A system could have an impact on development of therapies for important viral pathogens and cancer.Keywords 2-5A; RNase L; interferon; cancer; virus Background on the 2-5A/RNase L systemOver the past thirty-years, investigations into the mechanisms of interferon (IFN) action have elucidated how antiviral innate immunity operates within and between mammalian cells. The focus of my work over this period has been, and continues to be, probing the biology and biochemistry of the 2-5A/RNase L system, and studying its roles in health and disease. My scientific journey, from basic research to clinical studies, are summarized in this monograph. The 2-5A/RNase L system is one the principal pathways by which IFNs suppress viral infections. Exposure of cells to IFNs induces expression of genes that result in an "antiviral state". Type I IFNs bind to the IFN-α receptor 1 (IFNAR1) and IFNAR2 polypeptide chains on cell surfaces initiating JAK-STAT signaling to the IFN stimulated genes (ISGs) [1]. Included among over a hundred different ISGs are genes encoding 2-5A synthetases (OAS) [2,3]. The OAS genes are a family of ISGs that function in the 2-5A/RNase L system (Fig. 1). In humans there are three functional OAS genes (OAS1-3), resulting in 8 to 10 OAS isoforms due to alternative mRNA splicing [4]. In mice, in addition to OAS2 and OAS3 there are 7 separate OAS1 genes, including OAS1b, the flavivirus resistance gene (Flv r ] [5][6][7][8]. When stimulated by dsRNA, the functional OAS proteins produce a series of short 5′-phosphorylated, 2′,5′-linked oligoadenylates collectively referred to as 2-5A [p x 5′A(2′p5′A) n ; x = 1-3; n≥2] from ATP [9]. The first molecular clone for an OAS was obtained by Michel Revel's lab [10]. Biochemical characterization of OAS proteins by Ara Hovanessian's lab [11][12][13][14] and Ganes Sen's lab [15][16][17][18][19] and a crystal structure by Rune Hartmann and Vivien Yee (in collaboration with Ganes Sen and Just Justesen) [20] have led to functional and structural insight into the OAS family of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, type...

show abstract

Section: Background On the 2-5a/rnase L Systemmentioning

confidence: 99%

A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

Self Cite

View full text Add to dashboard Cite

show abstract

“…The expression patterns of genes encoding tyrosinase, tyrosinase related protein-2, pmel-17 and mart-1 HLA restricted, tumourassociated antigens are reported. Grey bars refer to IFN-α sensitive cell lines and black bars refer to IFN-α resistant lines (see Table 1 IFN-α (D10 +IFN and ME15+IFN, respectively) were used to assay cytokine modulated gene expression as matched with data obtained in fibrosarcoma cells (Der et al, 1998). Expression levels for each gene were calculated as normalized average difference (nAD) of fluorescence intensity as compared to hybridization to mismatched oligonucleotides, expressed in arbitrary units.…”

Section: Experimental Set Up and Detection Of Genes Encoding Tumour-amentioning

confidence: 99%

High density oligonucleotide array analysis of interferon-α2a sensitivity and transcriptional response in melanoma cells

et al. 2001

View full text Add to dashboard Cite

Summary Interferon alpha (IFN-α) represents an adjuvant therapy of proven effectiveness in increasing disease-free interval and survival in subgroups of melanoma patients. Since high doses of cytokine are required, the treatment is often accompanied by toxic side effects. Furthermore, naturally occurring insensitivity to IFN-α may hamper its therapeutic efficacy. Clinical, molecular or immunological markers enabling the selection of potential responders have not been identified so far. To explore the molecular basis of IFN-α responsiveness, we analysed the expression pattern of about 7000 genes in IFN-α sensitive and resistant cell lines and we compared the transcription profiles of cells cultured in the presence or absence of the cytokine using high-density oligonucleotide arrays. Melanoma cell lines were screened for their sensitivity to proliferation inhibition and HLA class I induction upon IFN-α treatment by standard 3H-thymidine incorporation and flowcytometry. The study of 4 sensitive and 2 resistant cell lines allowed the identification of 4 genes (RCC1, IFI16, hox2 and h19) preferentially transcribed in sensitive cells and 2 (SHB and PKC-ζ) preferentially expressed in resistant cells. IFN-α stimulation resulted in the expression of a panel of 19 known inducible genes in sensitive but not in resistant cells. Moreover a group of 30 novel IFN-α inducible genes was identified. These data may provide a useful basis to develop diagnostic tools to select potential IFN-α responders eligible for treatment, while avoiding unnecessary toxicity to non-responders. Furthermore, by extending the knowledge of the polymorphic effects of IFN-α on gene expression, they offer novel clues to the study of its pleiotropic toxicity.

show abstract

“…Interaction of type I IFN with the IFNAR results in activation of the receptor-associated kinases Tyk-2 and Jak-1, which phosphorylate the transcription factors Stat-1 and Stat-2 ( Figure 1). Stat-1 and Stat-2 associate with IRF-9 and form a complex (ISGF3) that interacts with IFNstimulated response elements in the promoters of hundreds of IFN-stimulated genes (24)(25)(26). Several other pathways are, however, also involved in the action of the IFNAR (24).…”

Section: Introductionmentioning

confidence: 99%