title: ARF and p53 coordinate tumor suppression of an oncogenic IFN-β-STAT1-ISG15 signaling axis.
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.
authors.affiliation: 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.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Forys
authors.affiliation: 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.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Kuzmicki
authors.affiliation: 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.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Saporita
authors.affiliation: 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.
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Winkeler
authors.affiliation: 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.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Maggi
authors.affiliation: 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.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Weber
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D016207:Cytokines; D050794:STAT1 Transcription Factor; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C074034:ISG15 protein, human; D016899:Interferon-beta; D020727:ADP-Ribosylation Factors
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