Elevated level of SUMOylated IRF-1 in tumor cells interferes with IRF-1-mediated apoptosis

doi:10.1073/pnas.0609852104

Elevated level of SUMOylated IRF-1 in tumor cells interferes with IRF-1-mediated apoptosis

*Molecular Therapy Research Center, Sungkyunkwan University, Seoul 135-710, Korea;
^†Korea Basic Science Institute, Gwangju 500-757, Korea;
^‡Research Institute, National Cancer Center, Gyeonggi-do 411-769, Korea;
^§Department of Life Science, Yong-In University, Gyeonggi-do 449-719, Korea; and
^¶Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea

Edited by Peter M. Howley, Harvard Medical School, Boston, MA, and approved September 12, 2007 (received for review November 7, 2006)

Abstract

SUMOylation of transcription factors often attenuates transcription activity. This regulation of protein activity allows more diversity in the control of gene expression. Interferon regulatory factor-1 (IRF-1) was originally identified as a regulator of IFN-α/β, and its expression is induced by viral infection or IFN stimulation. Accumulating evidence supports the theory that IRF-1 functions as a tumor suppressor and represses the transformed phenotype. Here we report that the level of SUMOylated IRF-1 is elevated in tumors. Site-directed mutagenesis experiments disclose that the SUMOylation sites of IRF-1 are identical to the major ubiquitination sites. Consequently, SUMOylated IRF-1 displays enhanced resistance to degradation. SUMOylation of IRF-1 attenuates its transcription activity, and SUMOylated IRF-1 inhibits apoptosis by repression of its transcriptional activity. These data support a mechanism whereby SUMOylation of IRF-1 inactivates its tumor suppressor function, which facilitates resistance to the immune response.

Footnotes

^‖To whom correspondence should be addressed. E-mail: jeholee{at}gmail.com
Author contributions: J.P. designed research; J.P., K.K., Y.-J.S., and S.-N.L. performed research; E.-J.L., S.B.R., S.-H.L., and J.-H.L. contributed new reagents/analytic tools; J.P., E.-J.L., K.P., S.-H.L., and J.-H.L. analyzed data; and J.P. and K.P. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0609852104/DC1.
Abbreviations:

IRF-1,

interferon regulatory factor-1;

ISRE,

interferon stimulated response element;

Luc,

luciferase;

MTT,

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide;

NEM,

N-ethylmaleimide.