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Cell Rep. 2014 Apr 24;7(2):514-526. doi: 10.1016/j.celrep.2014.03.026. Epub 2014 Apr 13.

ARF and p53 coordinate tumor suppression of an oncogenic IFN-β-STAT1-ISG15 signaling axis.

Author information

1
BRIGHT Institute, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA; Division of Molecular Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA.
2
BRIGHT Institute, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA; Division of Molecular Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Cell Biology and Physiology, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: jweber@dom.wustl.edu.

Abstract

The ARF and p53 tumor suppressors are thought to act in a linear pathway to prevent cellular transformation in response to various oncogenic signals. Here, we show that loss of p53 leads to an increase in ARF protein levels, which function to limit the proliferation and tumorigenicity of p53-deficient cells by inhibiting an IFN-β-STAT1-ISG15 signaling axis. Human triple-negative breast cancer (TNBC) tumor samples with coinactivation of p53 and ARF exhibit high expression of both STAT1 and ISG15, and TNBC cell lines are sensitive to STAT1 depletion. We propose that loss of p53 function and subsequent ARF induction creates a selective pressure to inactivate ARF and propose that tumors harboring coinactivation of ARF and p53 would benefit from therapies targeted against STAT1 and ISG15 activation.

PMID:
24726362
PMCID:
PMC4157460
DOI:
10.1016/j.celrep.2014.03.026
[Indexed for MEDLINE]
Free PMC Article

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