STAT1-independent inhibition of cyclooxygenase-2 expression by IFNγ; a common pathway of IFNγ-mediated gene repression but not gene activation

L. Klampfer, J. Huang, P. Kaler, T. Sasazuki, S. Shirasawa, Leonard H. Augenlicht

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of prostaglandins, promotes the development of colorectal cancer, and is a key molecular target of non-steroidal anti-inflammatory drugs, compounds that reduce the relative risk of developing colon cancer. In this study, we showed that interferon γ (IFNγ) inhibits the expression of COX-2 protein in intestinal epithelial cells (IECs) through a pathway that requires Janus-activated kinase (JAK) activity. In contrast, we demonstrated that transcriptional inhibition of COX-2 by IFNβ or IFNγ occurs in cells with silenced signal transducer and activator of transcription 1 (STAT1) expression and that IFNs retained the ability to inhibit COX-2 transcription in cells with activated RasV12, in which IFNγ failed to induce STAT1. Thus, unlike the activity of JAK, STAT1 is not required for the inhibition of COX-2 expression by IFNγ. In contrast to COX-2, the activation of genes in response to IFNγ, such as interferon regulatory factor-1, was severely impaired by both STAT1 silencing and by constitutive Ras signaling. To determine whether there is a general differential requirement for STAT1 in gene activation and gene repression in response to IFNγ in intestinal cells, we performed genome-wide analysis of IFNγ target genes in an IEC line in which STAT1 expression was silenced by small interfering RNA. The results confirmed that the activation of the majority of genes by IFNγ required STAT1. In contrast, the repression of several genes, as we showed for COX-2 specifically, was largely unaffected in cells with silenced STAT1. Our results therefore demonstrate that in general gene activation by IFNγ is more sensitive to STAT1 deficiency than gene repression, and suggest that IFNγ activates and represses gene expression via distinct pathways that can be distinguished, at least in part, by their requirement for STAT1.

Original languageEnglish (US)
Pages (from-to)2071-2081
Number of pages11
JournalOncogene
Volume26
Issue number14
DOIs
StatePublished - Mar 29 2007

Fingerprint

STAT1 Transcription Factor
Cyclooxygenase 2
Interferons
Transcriptional Activation
Genes
Janus Kinases
Epithelial Cells
Interferon Regulatory Factor-1
Colonic Neoplasms
Small Interfering RNA
Prostaglandins
Colorectal Neoplasms
Anti-Inflammatory Agents

Keywords

  • Colon cancer
  • COX-2
  • IFN
  • JAK
  • STAT1

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

STAT1-independent inhibition of cyclooxygenase-2 expression by IFNγ; a common pathway of IFNγ-mediated gene repression but not gene activation. / Klampfer, L.; Huang, J.; Kaler, P.; Sasazuki, T.; Shirasawa, S.; Augenlicht, Leonard H.

In: Oncogene, Vol. 26, No. 14, 29.03.2007, p. 2071-2081.

Research output: Contribution to journalArticle

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abstract = "Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of prostaglandins, promotes the development of colorectal cancer, and is a key molecular target of non-steroidal anti-inflammatory drugs, compounds that reduce the relative risk of developing colon cancer. In this study, we showed that interferon γ (IFNγ) inhibits the expression of COX-2 protein in intestinal epithelial cells (IECs) through a pathway that requires Janus-activated kinase (JAK) activity. In contrast, we demonstrated that transcriptional inhibition of COX-2 by IFNβ or IFNγ occurs in cells with silenced signal transducer and activator of transcription 1 (STAT1) expression and that IFNs retained the ability to inhibit COX-2 transcription in cells with activated RasV12, in which IFNγ failed to induce STAT1. Thus, unlike the activity of JAK, STAT1 is not required for the inhibition of COX-2 expression by IFNγ. In contrast to COX-2, the activation of genes in response to IFNγ, such as interferon regulatory factor-1, was severely impaired by both STAT1 silencing and by constitutive Ras signaling. To determine whether there is a general differential requirement for STAT1 in gene activation and gene repression in response to IFNγ in intestinal cells, we performed genome-wide analysis of IFNγ target genes in an IEC line in which STAT1 expression was silenced by small interfering RNA. The results confirmed that the activation of the majority of genes by IFNγ required STAT1. In contrast, the repression of several genes, as we showed for COX-2 specifically, was largely unaffected in cells with silenced STAT1. Our results therefore demonstrate that in general gene activation by IFNγ is more sensitive to STAT1 deficiency than gene repression, and suggest that IFNγ activates and represses gene expression via distinct pathways that can be distinguished, at least in part, by their requirement for STAT1.",
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