Review: The Role of IRF-4 in Transcriptional Regulation

Abstract

Gene expression is a tightly regulated process involving multiple levels of control spanning histone acetylation to protein turnover. One of the first events in this cascade is transcription, which itself is a multistep process involving protein-protein interaction and macromolecular assembly. Here we review the role of the interferon (IFN) regulatory factor (IRF) transcription factor family member IRF-4 in transcriptional regulation. IRF-4 was initially characterized in lymphocytes and was shown to function as both a transcriptional repressor and activator. More recently, IRF-4 expression and function have been reported in macrophages. The ability of IRF-4 to serve as both a transcriptional activator and repressor is determined, in part, by binding to distinct DNA-binding motifs and through interaction with various additional transcription factors, most notably with the Ets family member PU.1. The details governing these functional differences are the focus of this review. Importantly, the role of posttranslational modification and nuclear translocation of IRF-4 in transcriptional regulation are addressed. Several possible paradigms of transcriptional regulation by IRF-4 are proposed, where these paradigms may describe regulatory mechanisms common to many distinct transcription factor families.

IRF-4 Suppresses BCR/ABL Transformation of Myeloid Cells in a DNA Binding-independent Manner

“…One possible mechanism by which the DNA binding domain mutants of IRF-4 inhibit BCR/ABL transformation is that mutant IRF-4 sequestrates transcription factors that are critical for cell growth/survival. However, the interactions between IRF-4 and its transcription partners are weak and their stable interaction relies on DNA binding (1,27). As such, the DNA binding domain mutants of IRF-4 are unlikely to function as dominant negative regulators.…”

“…2 plays a critical role in B, T, and dendritic cell development as well as in immune response regulation (1,2). IRF-4 was also originally identified as a proto-oncogene resulting from a t(6;14)(p25;q32) chromosomal translocation in multiple myeloma (3).…”

“…IRF-4 can regulate many genes by interacting with a transcription factor PU.1, which is important in normal myeloid and lymphoid development (1,33,34). To test the importance of the IRF-4/PU.1 interaction for IRF-4 tumor suppressor activity, we checked the tumor suppressor activities of PU.1 binding mutants of IRF-4, AS397 and 1-380 (27, 35).…”

Negative regulation of Toll-like-receptor signaling by IRF-4

“…As an approach to further examine the significance of IRF-4, which selectively competes with IRF-5 for MyD88 interaction, we next generated two mutants, one lacking the regulatory domain (IRF-4⌬RD) (17,20) and the other lacking the DNA-binding domain (IRF-4⌬DBD), tagged with YFP (YFP-IRF-4⌬RD and YFP-IRF-4⌬DBD, respectively; Fig. 3a).…”

Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

“…18,31 Expression of Irf4 is restricted to cells of the immune system, including lymphocytes, dendritic cells and macrophages, in which it has been linked to a variety of functions, such as proliferation, apoptosis and differentiation. 33,34,49 Irf4 knockout mice have normal early B-cell development but profound reduction in serum immunoglobulin concentrations and show incapability to mount antibody responses because of a latestage blockage in peripheral B-cell maturation that leads to the absence of plasma cells, plasmablasts and classswitched B cells. 30,35 Recently, the Irf4 gene has been demonstrated to have a biphasic expression pattern: it is expressed in immature B cells in the bone marrow, 48 absent from proliferating germinal center centroblasts and then re-expressed in a subpopulation of centrocytes in the germinal center and in plasma cells.…”