Disease relevance of EGR2

• OBJECTIVE: To determine the frequency of EGR2 mutations in patients with a diagnosis of CMT1, Dejerine-Sottas syndrome (DSS), or unspecified peripheral neuropathies [1].
• Novel EGR2 mutation R359Q is associated with CMT type 1 and progressive scoliosis [2].
• Preliminary sequence analysis of the zinc finger motifs in these cDNAs indicate that they belong to a subclass of the Cys-Cys/His-His motif, showing the highest homology to the Wilm's tumor and EGR1, EGR2 cDNAs [3].
• Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes [4].
• Two missense mutations of EGR2 R359W and GJB1 V136A in a Charcot-Marie-Tooth disease family [5].

Psychiatry related information on EGR2

• Microsatellite marker D10S1225, associated with Alzheimer's disease, non-syndromic congenital retinal non-attachment (NCRNA) and non-syndromic autosomal recessive persistent hyperplastic primary vitreous (arPHPV), was located within the TRIP8-EGR2 locus [6].

High impact information on EGR2

• In support of this hypothesis, we have identified one recessive and two dominant missense mutations in EGR2 (within regions encoding conserved functional domains) in patients with congenital hypomyelinating neuropathy (CHN) and a family with Charcot-Marie-Tooth type 1 (CMT1) [7].
• The early growth response 2 gene (EGR2) is part of a multigene family encoding Cys2His2 type zinc-finger proteins and may play a role in the regulation of cellular proliferation [7].
• Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage [7].
• We hypothesized that Egr2 may be a transcription factor affecting late myelin genes and that human myelinopathies of the PNS may result from mutations in EGR2 [7].
• Stable expression of Egr2 is specifically associated with the onset of myelination in the peripheral nervous system (PNS) [7].

Biological context of EGR2

• Strikingly, the deduced amino acid sequences of human EGR2 and mouse Egr-1 are 92% identical in the zinc finger region but show no similarity elsewhere [8].
• EGR2 maps to human chromosome 10 at bands q21-22 [8].
• Using adenovirus-mediated gene transfer to 39 cancer cell lines, we found that EGR2 could induce apoptosis in a large proportion of these lines by altering the permeability of mitochondrial membranes, releasing cytochrome c and activating caspase-3, -8, and -9 [9].
• Colony-formation assays using plasmid clones designed to express each gene indicated that EGR2 and BPOZ were able to suppress growth of cancer cells significantly; in particular, cancer-cell lines stably expressing BPOZ grew more slowly than control cells containing mock vector [10].
• Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated [10].

Anatomical context of EGR2

• These data suggest that interaction between the Cx32 P2 promoter, SOX10, and EGR2 highlight a mechanism of peripheral nerve dysfunction [11].
• Although the expression of EGR2 mutants inhibits the transactivation of myelin gene promoters, the exact molecular mechanism by which these mutations cause the alteration of the myelination process is still unknown [12].
• Furthermore, in contrast to patients with typical DSN, patients with the EGR2 R359W mutation have more respiratory compromise and cranial nerve involvement [13].
• They were transiently co-transfected with NGFI-A, NGFI-C, Krox-20 and NGFI-B expression vectors in NG108-15, SN6 and COS-1 cells [14].
• Krox 20, expressed in myelinating but not promyelinating Schwann cells, is absolutely required for this transition, and myelination cannot occur in its absence [15].

Associations of EGR2 with chemical compounds

• EGR1 and EGR2 increased IL-3 promoter activity when the transfected cells were stimulated with phorbol-12-myristate-13-acetate and A23187 [16].
• Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression [4].
• The effect of coincubation with dibutyryl-cAMP (dBcAMP) was assessed in an attempt to prevent the colchicine-induced increase in PDGF(B) mRNA. dBcAMP alone resulted in no increase in PDGF(B) mRNA or alteration in TGF-beta mRNA but resulted in a reduction in EGR2 mRNA [17].
• PAF (10(-7) M) increased c-fos and EGR2 mRNA levels in cells suspended in Ca(2+)-containing medium by 6-10-fold [18].
• These neurons also showed persistent cyclic adenosine monophosphate response element binding protein (CREB) activation and nuclear translocation of EGR-2 and c-fos proteins [19].

Physical interactions of EGR2

• The D355V mutation decreases EGR2 binding to an element within the Cx32 promoter [20].
• These experiments demonstrate direct binding of Egr2 to previously described binding sites within the Schwann cell enhancer of the myelin basic protein gene [21].

Regulatory relationships of EGR2

• Known inducers of Mpz expression such as forskolin and insulin-like growth factor-1 also activate the element in an Egr2-dependent manner [22].

Other interactions of EGR2

• Our study shows that this factor, in synergy with EGR2, strongly activates Cx32 expression in vitro by directly binding to its promoter [23].
• Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway [10].
• A second group contains the regulators of myelin gene transcription EGR2/Krox20 and SOX10 [24].
• No mutation was detected in genes PMP22, EGR2 and LITAF among the remaining nine (28.1%) CMT1 patients [25].
• Dominant and recessive mutations in EGR2 are associated with peripheral myelinopathies, such as Charcot-Marie-Tooth disease type 1, Dejerine-Sottas syndrome, and congenital hypomyelinating neuropathy [26].

Analytical, diagnostic and therapeutic context of EGR2

• Molecular cloning, sequencing, and mapping of EGR2, a human early growth response gene encoding a protein with "zinc-binding finger" structure [8].
• Our results helped to clarify the molecular mechanism of the apoptotic pathway induced by PTEN-EGR2, and suggested that EGR2 may be an excellent target molecule for gene therapy to treat a variety of cancers [9].
• Using chromatin immunoprecipitation assays, we find that Egr2 binds in vivo to the intron element, but not to the Mpz promoter [22].
• We also show that changes in the expression of other ITFs (Fos, Jun-D and Krox-20) and the BDNF/trkB neurotrophin system may play a central role in the development of hippocampal kindling, an animal model of human temporal lobe epilepsy [27].
• Both Northern blot and in situ hybridization analyses demonstrated increased EGR-1, but not EGR-2 or EGR-alpha expression, in malignant prostate tissue as compared with weak expression in nonmalignant tissue [28].

References