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N-ras-induced growth suppression of myeloid cells is mediated by IRF-1

Toby Passioura1, Alla Dolnikov, Sylvie Shen

  • 1School of Medical Sciences, The University of New South Wales, Kensington, Sydney, New South Wales, Australia.

Cancer Research
|February 12, 2005
PubMed

Insights

Activating ras oncogenes can suppress myeloid cell growth and promote differentiation. This tumor suppressive response involves the transcription factor IFN regulatory factor-1 (IRF-1), which upregulates p21(CIP1/WAF1).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Activating mutations in ras oncogenes are common in human cancers.
  • Ras activation typically transforms cells, but paradoxically can cause growth suppression in some myeloid cell lines.
  • This growth suppression is linked to increased p21(CIP1/WAF1) independently of p16(INK4a), p15(INK4b), and p53.

Purpose of the Study:

  • To compare gene expression profiles of myeloid cells undergoing growth suppression versus transformation induced by activated N-ras.
  • To investigate the role of IFN regulatory factor-1 (IRF-1) in N-ras-mediated growth suppression and differentiation.

Main Methods:

  • Utilized cDNA array technology to analyze gene expression profiles.
  • Compared expression in growth-suppressed versus transformed myeloid cells expressing N-rasG13R.
  • Employed antisense suppression to inhibit IRF-1 function.

Main Results:

  • Gene expression in growth-suppressed cells indicated differentiation, including upregulation of IRF-1.
  • IRF-1 was identified as a transcriptional activator of p21(CIP1/WAF1) and a target in myeloid leukemia.
  • Antisense suppression of IRF-1 blocked N-rasG13R-induced growth arrest and p21(CIP1/WAF1) upregulation.

Conclusions:

  • Identified a novel tumor suppressive pathway activated by oncogenic ras signaling in myeloid cells.
  • Established a mechanistic link between oncogenic signaling, growth suppression, and differentiation via IRF-1 and p21(CIP1/WAF1).
  • Highlights IRF-1 as a key mediator in the context of ras-driven myeloid malignancies.

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