TY - JOUR
T1 - ARF and p53 Coordinate Tumor Suppression of an Oncogenic IFN-β-STAT1-ISG15 Signaling Axis
AU - Forys, Jason T.
AU - Kuzmicki, Catherine E.
AU - Saporita, Anthony J.
AU - Winkeler, Crystal L.
AU - Maggi, Leonard B.
AU - Weber, Jason D.
N1 - Funding Information:
We thank Scott Werneke and Deborah Lenschow for generously providing the ISG15 antibody. We also thank Michael Kuchenreuther, Alexander Miceli, and other members of the Weber laboratory for technical assistance. We are grateful to Josh Rubin and Greg Longmore for critical suggestions. This work was supported by National Institutes of Health (NIH) grant R01CA120436 and the Department of Defense Era of Hope Scholar grant to J.D.W. L.B.M. was supported by National Cancer Institute grant 1K12CA167540 and a Clinical and Translational Science Award (UL1RR024992) from the NIH. J.T.F. was supported by NIH grant 5T32GM007067.
PY - 2014/4/24
Y1 - 2014/4/24
N2 - 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 toinactivate ARF and propose that tumors harboringcoinactivation of ARF and p53 would benefit from therapies targeted against STAT1 and ISG15 activation.
AB - 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 toinactivate ARF and propose that tumors harboringcoinactivation of ARF and p53 would benefit from therapies targeted against STAT1 and ISG15 activation.
UR - http://www.scopus.com/inward/record.url?scp=84899629693&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2014.03.026
DO - 10.1016/j.celrep.2014.03.026
M3 - Article
C2 - 24726362
AN - SCOPUS:84899629693
SN - 2639-1856
VL - 7
SP - 514
EP - 526
JO - Cell Reports
JF - Cell Reports
IS - 2
ER -