The Egr transcription factor family

The family of Early Growth Response (Egr) transcription factors is a group of four transcription factors now named Egr1-4 that share a highly conserved DNA-binding domain consisting of three zinc-finger motifs. This domain recognizes a 9 base pair DNA segment, whereby each zinc finger recognizes three nucleotides 153, 154, 155, 156, 157, 158, 159, 160, 161

. Apart from this conserved domain, Egrs differ in their structure to varying degrees. Egr2 and Egr3 are the most closely related, followed by Egr1 and Egr4 which are more distantly related ¹⁶². Egr3 is the only member of the Egr transcription factor family for whom the presence of several isoforms has been reported ^{163, 164}.

In general, these transcription factors are rapidly induced mainly in response to growth factor stimulation, but other stress-related stimuli have also been shown to induce Egr transcription factors. The expression of the Egr transcription factors appears to be tightly regulated, as stimuli inducing Egrs also induce the nuclear co-repressor NGFI-A binding protein-2 (NAB2) that suppresses transcriptional activity of Egr1, Egr2 and Egr3, whereby it has been shown that they also induce their suppressor NAB2 154, 165, 166. Regulation of Egr4 differs from that of the other members of the Egr family, as it does not contain a NAB2-binding site. Instead, Egr4 appears to have autoregulatory properties, as it binds a region in its own promoter and represses its own transcription

167.

The Egr transcription factors seem to fulfill different functions in different processes. In general, they are thought to be involved in processes such as cell survival, proliferation, differentiation, and apoptosis ¹⁵⁴.

Much research has focused on the role of Egrs in neurons with regard to neuronal differentiation, memory and learning ¹⁶². Egr1, Egr2 and Egr3 are rapidly upregulated in neuronal cells after stimulation of the cells by induction of long-term potentials (LTPs)

162, 168, 169, 170, 171. Furthermore, much research has been performed in Egr-deficient mice, which are viable, except for mice lacking Egr2. Mice lacking Egr1 and Egr4 show problems with fertility, whereas mice lacking Egr3 have severe motor abnormalities due to lack of muscle spindles 153, 172, 173, 174, 175, 176, 177

. Mice lacking Egr1 show deficiencies in maintenance of late LTPs and interestingly, they are unable to form long term memories as tested in a variety of behavioral tasks. However, no impairment in short-term memory formation was found ^{178, 179}. This is in contrast to Egr3-deficient mice that show deficits in short-term memory formation and as a consequence, also in long-term memory formation. These defects are in addition to the previously mentioned motor abnormalities and abnormal reaction and adaptation to stress and in social interactions

162, 180, 181

. The involvement in neurological processes of the Egr transcription factors is reminiscent with human association studies that indicate an involvement of Egr1 with Alzheimer’s disease and Egr3 in Schizophrenia in several populations, as well as in Bipolar Disorder and even psychosis 182, 183, 184, 185, 186, 187, 188, 189, 190, 191. Additionally, Egr2 and Egr3 are involved in immunity as they contribute to the regulation of proliferation and differentiation of B and T cells and also of dendritic cells 192, 193, 194, 195

.

Since Egr1 and Egr3 are involved in proliferation, they have also been found to play a role in cancer. However, for Egr1, opposing roles have reported in different types of cancer. In prostate cancer cells, Egr1 is overexpressed and has been shown to be required for tumor progression 22, 196, 197, 198

. In a transgenic mouse model, loss of Egr1 delayed tumor progression from neoplasia to invasive carcinoma. Generally, Egr1 is overexpressed in prostate cancer and promotes tumor progression, possibly by controlling proteins involved in cell cycle regulation such as Cyclin D2. Egr1 also induces other proteins important for tumor progression such as insulin-like growth factor-II, transforming growth factor-β1 (TGF- β1), and platelet-derived growth factor-A.

In addition, Egr1 promotes translocation of the androgen receptor to the nucleus ^{154, 198,}

199, 200, 201, 202, 203, 204, 205. Furthermore, the Egr1 repressor Nab2 is downregulated in both human and mouse prostate tumors ²⁰⁶. In contrast, in several other types of cancer including breast cancer, Egr1 was lost 207, 208, 209, 210, 211

. Interestingly, in breast cancer, Egr1 was found to induce expression of the tumor suppressor BRCA1 ²¹². In general, in some cancers, Egr1 might act as a tumor suppressor and inhibit tumor progression, while in other cancer types, Egr1 is overexpressed, promotes tumor progression and was even shown to enhance drug resistance of the tumor 210, 213, 214, 215, 216, 217, 218

. Of note, apoptosis induction by several chemotherapeutic agents was shown to be mediated by Egr1 219, 220, 221, 222

. More research is required to integrate these opposing findings into a coherent model of Egr1 function.

Research on the involvement of Egr3 in cancer has been less extensive so far, but it was found to play a role in prostate cancer and breast cancer. Egr3 was found to be highly overexpressed in non-relapsing prostate cancer, but showed lower expression in relapsing prostate cancer. In addition, expression patterns of inflammatory genes that are known to be involved in prostate cancer correlated with Egr3 expression levels, indicating a regulatory role for Egr3. Upregulation of inflammatory cytokines and growth factors, in particular of Interleukin-6 (IL6) and IL8 was found to be Egr3 dependent in prostate cancer by a later study, and this was suggested to be an important part of prostate cancer progression ^{223, 224}. In breast cancer, Egr3 was shown to be induced by estrogen-mediated signaling, and increased expression of Egr3 in patient samples was

associated with an increased risk of recurrence of the cancer as well as an adverse clinical outcome. These correlations are in line with the finding that overexpression of Egr3 increased cancer cell migration and invasion properties ^{225, 226}. In contrast, in gastric cancer, Egr3 was found to be expressed at lower levels compared with matched non-tumour tissues, and decreased Egr3 expression levels correlated with poor prognosis ²²⁷.

2 Integration of extracellular signaling to the early