Interferon regulatory factor 1 inactivation in human cancer

Abstract

Interferon regulatory factors (IRFs) are a group of closely related proteins collectively referred to as the IRF family. Members of this family were originally recognized for their roles in inflammatory responses; however, recent research has suggested that they are also involved in tumor biology. This review focusses on current knowledge of the roles of IRF-1 and IRF-2 in human cancer, with particular attention paid to the impact of IRF-1 inactivation. The different mechanisms underlying IRF-1 inactivation and their implications for human cancers and the potential importance of IRF-1 in immunotherapy are also summarized.

Keywords: Cancer; Interferon Regulatory Factor; Oncogene; Tumor Suppressor.

Figure 1. Illustration of the various functional domains of IRF family members

All IRF family members contain a DBD (blue) and a regulatory domain (light blue). In addition, most IRFs possess a type 1 (dark green) or type 2 (light green) IAD. A repression domain that functions to repress gene expression (purple) is also present in some IRF family members. Finally, a nuclear localization signal domain (orange) is found in most IRFs.

Figure 2. The anti- and pro-oncogenic activity of IRF-1 and IRF-2

IRF-1 anti-oncogenic activity is attributed to four main mechanisms: (I) Derailing of cell cycle; (II) Down-regulation of growth promoting genes; (III) Induction of tumor suppressor genes, and (IV) Up-regulation of apoptotic machinery. The pro-oncogenic potential of IRF-2 is owed to: (i) Suppression of IRF-1 activity; (ii) up-regulation of growth promoting genes, and (iii) supporting oncogenes-induced growth.

Figure 3. Signal transduction pathway and cross-talk in the interferon system

Stimulation of type I and II interferon receptor recruits Janus and tyrosine kinases that phosphorylates and activates STAT. STAT proteins trigger nuclear translocation of IRF members where they interact with ISRE to regulate expression of ISG resulting in various physiological responses.