Disease relevance of MBD2

• These findings implicate MBD2 in GSTP1 silencing associated with somatic GSTP1 CpG island hypermethylation in breast cancer cells [1].
• These findings suggest that the transcriptional silencing of the 14-3-3sigma gene is caused by promoter CpG island methylation associated with MBD2, and that this may play an important role in prostate cancer progression during the invasive and metastatic stages of the disease [2].
• MBD1, MBD2 and CGBP genes at chromosome 18q21 are infrequently mutated in human colon and lung cancers [3].
• In early-stage NSCLC (n = 70) expression of MeCP2 and MBD2 was significantly lower in squamous cell carcinoma than in adenocarcinoma or large cell carcinoma (P = 0.03 and P = 0.01) [4].
• These findings validate MBD2 as a potential target for therapeutic intervention in colorectal cancer [5].

High impact information on MBD2

• Importantly, studies in zebrafish and primary mammalian neurons demonstrated a role for SMCX in neuronal survival and dendritic development and a link to the demethylase activity [6].
• The recently identified histone demethylase lysine-specific demethylase 1 (LSD1) is chemically restricted to demethylation of only mono- and di- but not trimethylated histone H3 lysine 4 (H3K4me3) [6].
• Sited-directed mutagenesis in conjunction with demethylase activity assays allowed us to propose a molecular model for substrate selection by the JMJD2 histone demethylase family [7].
• They showed that LSD 1, a nuclear amine oxidase homolog, is a bona fide histone H3 lysine 4 demethylase (Shi et al., 2004) [8].
• The results thus identify a histone demethylase conserved from S. pombe to human and reveal dynamic regulation of histone methylation by both histone methylases and demethylases [9].

Chemical compound and disease context of MBD2

• Interestingly, more malignant MDA-MB- 231 human breast cancer cells have a more prominent loss of DNA methylation accompanied by altered expression of maintenance DNA methyltransferase DNMT1, methyl-binding proteins MeCP2 and MBD2, decreased trimethylation of lysine 20 of histone H4 and hyperacetylation of histone H4 compared to MCF-7 cells [10].
• The metabolism of trimethylamine (TMA) and dimethylamine (DMA) in Arthrobacter P1 involved the enzymes TMA monooxygenase and trimethylamine-N-oxide (TMA-NO) demethylase, and DMA monooxygenase, respectively [11].
• However, new triazole antifungal compounds, which are potent inhibitors of the sterol C14alpha demethylase of the parasite and have special pharmacokinetic properties, are capable of inducing parasitological cures in murine models of both acute and chronic Chagas disease [12].

Biological context of MBD2

• Our report concerns MBD2, which can bind methylated DNA in vivo and in vitro and has been reported to actively demethylate DNA (ref. 8). As DNA methylation causes gene silencing, the MBD2 demethylase is a candidate transcriptional activator [13].
• The data demonstrate that MBD2 and MBD4 bind specifically to methyl-CpG in vitro and in vivo and are therefore likely to be mediators of the biological consequences of the methylation signal [14].
• Transient overexpression of MBD2 suppressed luciferase activity specifically from the methylated rRNA promoter, whereas MBD1 and MBD3 inhibited rRNA promoter activity irrespective of the methylation status [15].
• Chromatin immunoprecipitation analysis confirmed predominant association of MBD2 with the endogenous methylated rRNA promoter, which suggests a selective role for MBD2 in the methylation-mediated inhibition of ribosomal RNA gene expression [15].
• Four of seven zinc fingers present in the C-terminal region of MIZF are required for binding with MBD2 [16].

Anatomical context of MBD2

• Our data suggest that HeLa cells, which lack the known methylation-dependent repressor MeCP2, use an alternative pathway involving MBD2 to silence methylated genes [13].
• However, there was no protein expression for MBD2 and MeCP2 in cancer cell lines and cancer tissues [17].
• In both male and female fetal gonads expression of genes for MBD2 and MBD4, which may be implicated in chromatin remodeling of methylated genomic DNA sequences, was tightly linked to DNMT expression [18].
• Slightly reduced expression of MBD2 was detected in HCCs, and the expression of MeCP2 was particularly reduced in HCCs with portal vein involvement [19].
• No significant changes in MeCP2 or MBD2 expression were found when NB4 cells were differentiated toward granulocytes suggesting that neither differentiation nor cell cycle status were relevant for the reduced expression of these genes in human cancer [4].

Associations of MBD2 with chemical compounds

• Exogenous MBD2 represses transcription in a transient assay, and repression can be relieved by the deacetylase inhibitor trichostatin A (TSA; ref. 12) [13].
• In vivo, MBD3L1 associates with and colocalizes with MBD2 but not with MBD3 and is recruited to 5-methylcytosine-rich pericentromeric heterochromatin in mouse cells [20].
• Treatment of cancer cell lines with proteasome inhibitor (MG-132) did not restore expression of MBD2 and MeCP2 proteins [17].
• Methyl-CpG binding domain protein 2 represses transcription from hypermethylated pi-class glutathione S-transferase gene promoters in hepatocellular carcinoma cells [21].
• Fully methylated but not unmethylated GSTP1 promoter fragment was shown to bind to a complex similar to methyl cytosine-binding protein complex 1 that contains methyl-CpG-binding domain 2 protein (MBD2) in electrophoretic mobility shift assays using LNCaP cell nuclear extracts [22].

Physical interactions of MBD2

• An affinity-purified HDAC1 corepressor complex also contains MBD2, suggesting that MeCP1 corresponds to a fraction of this complex [13].
• MBD3 does not directly bind methylated DNA but is highly related to MBD2, a polypeptide that binds to methylated DNA and has been reported to possess demethylase activity [23].
• Moreover, by a co-immunoprecipitation experiment, DNMT1 was shown to form a complex with MBD2 and MBD3 [24].
• The methylated-CpG island recovery assay (MIRA), which is based on the high affinity of the MBD2/MBD3L1 complex for methylated DNA, has been used to detect cell type-dependent differences in DNA methylation on a microarray platform [25].
• AIM: To explore the effect of DNA methyltransferase, demethylase and methyl-CpG binding protein MeCP2 on the expressions and methylation of hMSH2 and proto-oncogene in human gastric cancer [26].

Regulatory relationships of MBD2

• MBD3L1 enhances transcriptional repression of methylated DNA by MBD2 [20].
• The results of this study demonstrate that MBD2 gene is expressed in all samples and MeCP2 gene is expressed in all cancer cell lines but not in BPH-1 cell line [17].
• We hypothesize that MBD2 enzyme activity is repressed and that DNMT1 enzyme activity is elevated in human prostate cancer [27].
• The Gal4-linked TRD of the related methyl-CpG-binding protein MBD1 also repressed transcription but not that of MBD2 [28].
• Overexpression of RAR in MKN-28 cells appeared to regulate the expression of DNA methyltransferase and DNA demethylase and the acetylation of hitone H4 [29].

Other interactions of MBD2

• Expression of MBD2 and MBD4 tagged with green fluorescent protein in mouse cells shows that both proteins colocalize with foci of heavily methylated satellite DNA [14].
• MBD2 and MBD3 are two proteins that contain methyl-CpG binding domains and have a transcriptional repression function [30].
• The (m)CpG-binding protein MBD2 was associated only with the HDAC1 cII core complex [31].
• MeCP2, MBD1 and MBD2 can also repress transcription [32].
• Methyl-CpG-binding domain protein-2 mediates transcriptional repression associated with hypermethylated GSTP1 CpG islands in MCF-7 breast cancer cells [1].

Analytical, diagnostic and therapeutic context of MBD2

• Chromatin immunoprecipitation analysis detected the presence of MBD2 and DNMT1 at the GSTP1 promoter in MCF-7 breast cancer cells but not in MCF-7/ADR breast cancer cells [1].
• A direct interaction between MBD2 and MIZF was confirmed by in vitro binding assays and immunoprecipitation experiments [16].
• In the current case-control study, the authors investigated the association between MBD2 expression and bladder carcinoma risk [33].
• We examined levels of DNA methyltransferase (DNMT1, DNMT3a, DNMT3b) and DNA demethylase (MBD2) mRNA expression by semi-quantitative RT-PCR [34].
• Furthermore, confocal microscopy shows a nuclear colocalization of hp66alpha with hp66beta and MBD2 in a speckled pattern. hp66alpha is a potent transcriptional repressor reducing gene activity about 100-fold and is ubiquitously coexpressed with hp66beta in cell lines and in fetal and adult tissues [35].

References