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Tumor suppression by IFN regulatory factor-1 is mediated by transcriptional down-regulation of cyclin D1

Andrea Kröger1, Anja Stirnweiss, Julia Elisabeth Pulverer

  • 1Department of Gene Regulation and Differentiation, Helmholtz Center for Infection Research, Braunschweig, Germany. andrea.kroger@helmholtz-hzi.de

Cancer Research
|April 6, 2007
PubMed

Insights

Interferon regulatory factor-1 (IRF-1) reverses oncogenic gene expression, inhibiting cell proliferation and tumor growth by targeting cyclin D1. This reveals IRF-1

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Interferons (IFNs) exhibit antitumor properties.
  • Interferon regulatory factor-1 (IRF-1) is a key IFN-stimulated gene involved in tumor suppression.
  • Oncogenic transformation by c-myc and H-ras deregulates numerous genes, including those controlling cell cycle progression.

Purpose of the Study:

  • To investigate the role of IRF-1 in reversing oncogene-induced gene expression changes.
  • To elucidate the mechanisms by which IRF-1 inhibits cell proliferation and oncogenic transformation.
  • To identify key downstream targets of IRF-1 in tumor suppression.

Main Methods:

  • Analysis of mRNA expression profiles in oncogenically transformed cells with and without IRF-1 activation.
  • Assessment of cell cycle regulatory genes, including cyclin D1.
  • Evaluation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway activity.
  • In vitro assays and tumor xenograft models in nude mice to assess tumor growth and transformation.

Main Results:

  • IRF-1 reverted approximately 60% of deregulated mRNAs in c-myc and H-ras transformed cells to normal levels.
  • IRF-1 activation decreased cyclin D1 expression and cyclin-dependent kinase 4 (CDK4) activity, impacting retinoblastoma protein (Rb) phosphorylation.
  • IRF-1 inhibited the MAPK/ERK pathway and transcriptionally repressed cyclin D1.
  • Ectopic cyclin D1 expression overcame IRF-1-mediated tumor suppression, while cyclin D1 knockdown prevented transformation and tumor growth.

Conclusions:

  • IRF-1 plays a critical role in reversing oncogene-induced gene expression alterations.
  • IRF-1 exerts tumor-suppressive effects primarily through the inhibition of cell cycle progression.
  • Cyclin D1 is identified as a crucial direct target mediating the antitumorigenic functions of IRF-1.

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