E2F4

E2F4 Full Name

E2F transcription factor 4, p107/p130-binding

E2F4 Introduction

E2F4 is a member of the E2F family of transcription factors, the proteins that control the expression of the genes required for cell cycle progression and that sit at the center of the network regulating cell proliferation. The E2F family is divided into activators, such as E2F1, E2F2, and E2F3, which turn on genes in proliferating cells, and repressors, principally E2F4 and E2F5, which silence those same genes in quiescent and differentiating cells. E2F4 accomplishes this repression by binding, together with its dimerization partner of the DP family, to the promoters of cell cycle genes and recruiting the pocket proteins p107 and p130, which in turn bring in histone-modifying enzymes that compact chromatin and block transcription. Because E2F4 is expressed throughout the cell cycle and is the most abundant E2F family member in many cell types, it is the principal executor of the transcriptional repression that keeps cells in a resting state and that accompanies terminal differentiation. Beyond its classical role in the cell cycle, E2F4 has been implicated in the control of genes involved in DNA repair, apoptosis, and metabolism, and it can both promote and suppress tumor development depending on context. The importance of E2F4 in human biology is underscored by the phenotypes of mice lacking the gene, which show defects in the development of the gut, blood, and other tissues, and by its altered expression in human cancers.

Figure 1. The structure of E2F4.

DNA-Binding and Repression Machinery of E2F4
E2F4 belongs to the E2F family of transcription factors, all of which share a conserved DNA-binding domain that recognizes the E2F consensus sequence found in the promoters of cell cycle genes.
To bind DNA with high affinity, E2F4 must form a heterodimer with a DP partner protein (DP1 or DP2), and the E2F-DP dimer recognizes its target sites with much greater stability than either protein alone.
The C-terminal region of E2F4 contains the sequences that mediate binding to the pocket proteins p107 and p130, and this interaction is the basis of E2F4's function as a transcriptional repressor.
When cells enter quiescence or differentiate, hypophosphorylated p107 and p130 bind E2F4 at target promoters and recruit histone deacetylases and other chromatin-modifying complexes, silencing the expression of proliferation genes.
In proliferating cells, cyclin-dependent kinases phosphorylate the pocket proteins, releasing E2F4 and allowing activator E2Fs to occupy the promoters and drive transcription.
The E2F4 gene is located on human chromosome 16, and the protein is expressed widely, with particularly high levels in tissues that contain many quiescent or differentiated cells.
E2F4 can shuttle between the nucleus and the cytoplasm, and its nuclear import and export are regulated in a cell-cycle-dependent manner that controls its access to target promoters.

Quiescence, Differentiation, and Roles in Development and Cancer
E2F4-mediated repression is required for cells to enter and maintain quiescence, the reversible resting state from which they can be recalled to divide, and loss of E2F4 allows inappropriate expression of cell cycle genes in resting cells.
During differentiation, E2F4 helps silence the proliferation program as cells commit to their mature fates, and it is particularly important in tissues such as the gut, where epithelial cells constantly renew and differentiate.
Mice lacking E2F4 are viable but show defects in the development of the intestinal epithelium, the hematopoietic system, and other tissues, and they are predisposed to certain epithelial abnormalities.
The subcellular localization of E2F4 changes as cells differentiate: it moves to the cytoplasm in many postmitotic cells, and this relocalization is thought to contribute to the stable repression of the proliferation program.
In cancer, E2F4 can act as either a tumor suppressor or a promoter depending on the cellular context: loss of its repressive function may contribute to uncontrolled proliferation, whereas in some tumors cytoplasmic sequestration or altered splicing of E2F4 changes its activity.
Because the balance between E2F activators and repressors determines whether cells divide, therapeutic strategies that strengthen E2F4-mediated repression are being explored as a way to restrain the growth of cancer cells.

Alternate Names for E2F4

E2F4; E2F transcription factor 4, p107/p130-binding; transcription factor E2F4; E2F 4; p107/p130-binding protein; E2F-4;