Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysregulation of CpG-methylation is a common feature of many human cancers and tumour suppressor genes can be silenced by hypermethylation. Recently, 2 methyl-CpG-binding domain proteins have been linked to gene inactivation by their ability to recruit co-repressors and HDAC-activity to methylated gene promoters. Here, we have analysed mRNA expression of these genes, MeCP2 and MBD2, in a wide variety of primary human tumours. In solid tumours, expression levels of MBD2 (57/71) and MeCP2 (64/71) were significantly reduced in the majority of primary tumours as detected by quantitative real-time RT-PCR. Western blot analyses of MeCP2 in matched tumour-normal samples of patients with non-small-cell lung cancer (NSCLC) indicated reduced protein in a significant percentage of patients. In acute myelogenous leukaemia (n = 26), expression levels were only slightly reduced and did not differ between samples analysed at diagnosis or at the time of relapse. 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). To further elucidate the mechanisms of gene regulation, we analysed MeCP2 and MBD2 regulation during haematopoietic differentiation. 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. In conclusion, the significant loss of MeCP2 and MBD2 expression in human cancers suggests a potential role of this phenomenon in the development of solid human tumours.
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PMID:Loss of expression of HDAC-recruiting methyl-CpG-binding domain proteins in human cancer. 1171 Aug 31

The genes MBD1 and MBD2 encode methyl-CpG binding proteins that suppress transcription from methylated promoters. In contrast, CGBP encodes a protein that binds promoters containing unmethylated CpG and stimulates transcription. All three are located on human chromosome 18q21, a region of frequent loss of heterozygosity in several cancers. These genes therefore represent candidate tumour suppressor genes, whose loss of function could affect the normal regulation of gene expression, whether by lack of complete suppression of genes normally silenced (via loss of MBD1 and MBD2) or by some loss of activation of genes normally expressed (via loss of CGBP), either way contributing to the tumorigenic phenotype. We have confirmed by fluorescent in situ hybridization that MBD1 and MBD2 bracket the DCC locus giving a gene order of MBD1/CGBP-DCC 5'-DCC 3'-MBD2. Mutation analyses by single-stranded conformation polymorphism in colon and lung cancer cell lines and primary tumours revealed a small number of mutations, suggesting only a limited role of these genes in human tumorigenesis.
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PMID:MBD1, MBD2 and CGBP genes at chromosome 18q21 are infrequently mutated in human colon and lung cancers. 1277 3

DNA methylation is an epigenetic mechanism involved in transcriptional silencing of imprinted genes, genes located on the inactive X chromosome, and a number of tumour suppressor genes in cancer. MBD (methyl-CpG-binding domain) proteins selectively bind to methylated DNA and recruit chromatin remodelling and transcriptional repressor complexes, thereby establishing a repressive chromatin state. MBD2, a member of the MBD protein family, binds to methylated promoter CpG islands (clusters of high-density CpG dinucleotides) and acts as a methylation-dependent transcriptional repressor. Previous work has demonstrated that decreased CpG island methylation in mice lacking the DNA methyltransferase DNMT1 is associated with impaired tumorigenesis when crossed on the tumour-susceptible Apc(Min/+) background. Mbd2 deficiency also dramatically reduces adenoma burden and extends life span in a gene dosage-dependent manner in this mouse model. Mbd2 is therefore essential for tumorigenesis in the murine intestine, although it is dispensable for the viability of the host animals. These findings validate MBD2 as a potential target for therapeutic intervention in colorectal cancer.
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PMID:Role of MBD2 in gene regulation and tumorigenesis. 1624 64