Roles and regulations of the ETS transcription factor ELF4/MEF

Abstract

Most E26 transformation-specific (ETS) transcription factors are involved in the pathogenesis and progression of cancer. This is in part due to the roles of ETS transcription factors in basic biological processes such as growth, proliferation, and differentiation, and also because of their regulatory functions that have physiological relevance in tumorigenesis, immunity, and basal cellular homoeostasis. A member of the E74-like factor (ELF) subfamily of the ETS transcription factor family-myeloid elf-1-like factor (MEF), designated as ELF4-has been shown to be critically involved in immune response and signalling, osteogenesis, adipogenesis, cancer, and stem cell quiescence. ELF4 carries out these functions as a transcriptional activator or through interactions with its partner proteins. Mutations in ELF4 cause aberrant interactions and induce downstream processes that may lead to diseased cells. Knowing how ELF4 impinges on certain cellular processes and how it is regulated in the cells can lead to a better understanding of the physiological and pathological consequences of modulated ELF4 activity.

Keywords: ELF4; ETS transcription factors; cancer; immune regulation; myeloid elf-1-like factor (MEF); transcriptional regulation.

Figure 1

Functional, interacting, and modified residues of ELF4 protein. (A) ELF4 has 663 amino acid residues. Numbers are amino acid residues. P, phosphorylation; S, SUMOylation; Ub, ubiquitination; NLS, nuclear localization signal. (B) ELF4 interacts or is fused with various proteins at the indicated amino acid residues. AML1, PML, and STING proteins interact with ELF4. Fusions with ERG-1 and BCORL1 result from chromosomal translocation and inversion, respectively. Inset, fused regions of BCORL1 and ELF4. The C-terminal region of ELF4 (395−663 amino acids) is fused with most of BCORL1 (1−1618 amino acids). PRD, proline-rich domain; ANK, tandem ankryin repeats; NR boxes, nuclear receptor recruitment motifs. The indicated domains are not drawn to scale.

Figure 2

The roles of ELF4. (A) ELF4 is necessary for the development and function of NK cells. (B) During viral infection, ELF4 interacts with the immune signalling adaptor STING and is recruited to the STING−MAVS−TBK1 complex. TBK1 phosphorylates ELF4, resulting in the translocation of ELF4 to the nucleus where it binds to and activates type I IFN promoters cooperatively with IRF-3 and IRF-7. (C) ELF4 inhibits RUNX2-mediated and BMP-2 signalling-dependent differentiation of osteoblasts. ELF4 enhances PPAR-γ-induced differentiation of adipocytes. (D) ELF4 drives hematopoietic stem cells (HSCs) from quiescent state (G0) to G1 phase and promotes the cell cycle progression from G1 to S phase. (E) ELF4 and P53 transcriptionally activate MDM2, which is the E3 ligase of both ELF4 and P53.

Figure 3

The regulations of ELF4. (A) The transcriptional regulation of ELF4. ELF4 is targeted by various transcription factors in its promoter and enhancer regions. (B) The post-translational regulations of ELF4. ELF4 protein is subject to modifications that lead to its activation, dampening of activity (inhibition), or degradation. Phosphorylation by ATM kinase leads to the degradation of ELF4 (broken arrow).