ARF and p53 coordinate tumor suppression of an oncogenic IFN-β-STAT1-ISG15 signaling axis
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Published on: December 30, 2025
Jason T Forys1, Catherine E Kuzmicki1, Anthony J Saporita1
1BRIGHT 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.
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.
Insights
Loss of p53 increases ARF protein, which limits tumor growth by blocking the IFN-β-STAT1-ISG15 pathway. Tumors with both p53 and ARF loss benefit from therapies targeting STAT1 and ISG15.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- The ARF and p53 tumor suppressors traditionally act in a linear pathway to prevent cellular transformation.
- Understanding the interplay between ARF and p53 is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the functional relationship between ARF and p53 in cancer.
- To identify novel therapeutic targets in triple-negative breast cancer (TNBC) with p53 and ARF co-inactivation.
Main Methods:
- Analysis of p53-deficient cells and human TNBC tumor samples.
- Assessment of ARF protein levels and signaling pathway activity (IFN-β-STAT1-ISG15 axis).
- Evaluation of STAT1 depletion effects in TNBC cell lines.
Main Results:
- Loss of p53 elevates ARF protein levels.
- ARF inhibits the IFN-β-STAT1-ISG15 signaling axis, limiting proliferation and tumorigenicity in p53-deficient cells.
- TNBC tumors with p53 and ARF co-inactivation show high STAT1 and ISG15 expression and are sensitive to STAT1 depletion.
Conclusions:
- Loss of p53 and subsequent ARF induction creates selective pressure for ARF inactivation.
- Tumors with ARF and p53 co-inactivation may benefit from therapies targeting STAT1 and ISG15 activation.
- This study reveals a non-linear interaction between ARF and p53 with therapeutic implications for TNBC.
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