MBD2 deficiency does not accelerate p53 mediated lymphomagenesis

Sansom, Owen J.; Bishop, Stefan Mark; Bird, Adrian; Clarke, Alan R.

doi:10.1038/sj.onc.1208166

Cited by 17 publications

(8 citation statements)

References 13 publications

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“…In terms of cancer predisposition, the hypothesis being pursued is that the absence of these proteins will reduce the likelihood of epigenetic inactivation of key tumour-suppressor genes. Consistent with this hypothesis, we have shown that deficiency of one family member, Mbd2, specifically and dramatically reduces adenoma burden in the Apc Min mouse [25,26]. More recently, we have shown that Mbd2 plays a normal role in controlling correct spatial gene expression in the intestine [27].…”

Section: Epigenetic Modulation Of Tumorigenesis In the Intestinesupporting

confidence: 52%

Cancer genetics: mouse models of intestinal cancer

Clarke

2007

Biochemical Society Transactions

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The capacity to model cancer within the mouse has advanced significantly in recent years. Perhaps the most notable technical gains have been in the development of techniques that allow the temporal and spatial control of gene expression, so that it is now possible to regulate target genes in the tissue of choice and at a given time [Maddison and Clarke (2005) J. Pathol. 205, 181-193; Shaw and Clarke (2007) DNA Repair 6, 1403-1412; Marsh and Clarke (2007) Expert Rev. Anticancer Ther. 7, 519-531]. We have used these approaches to study tumorigenesis in the murine intestine. Loss of function of the tumour-suppressor gene Apc (adenomatous polyposis coli) has been associated with the development of both human and murine neoplasia, principally those of the intestinal epithelium. However, as Apc has been implicated in multiple cellular functions, the precise mechanisms underlying these associations remain somewhat unclear. I review here the use of an inducible strategy to co-ordinately delete genes from the adult murine epithelium. This approach has allowed a characterization of the direct consequences of inactivation of gene function. For Apc, these include failure in the differentiation programme, failure to migrate, aberrant proliferation and the aberrant induction of apoptosis. Transcriptome analysis of this model has also identified potential new targets for therapeutic intervention, such as Sparc (secreted protein acidic and rich in cysteine), deficiency of which, we have now shown, suppresses adenoma formation. Finally, we have been able to address how other genes modulate the consequences of Apc loss. Thus we show that there is little effect following loss of cyclin D1, Tcf-1 and p53, but that there are marked differences following loss of either c-Myc or Mbd2. The models therefore allow us to define the earliest events associated with carcinogenesis in the intestine.

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Section: Epigenetic Modulation Of Tumorigenesis In the Intestinesupporting

confidence: 52%

Cancer genetics: mouse models of intestinal cancer

Clarke

2007

Biochemical Society Transactions

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“…50 Importantly, deficiency of MBD2 does not recapitulate this phenotype, with no alteration in the predisposition to lymphomagenesis either alone or in the context of a null p53 mutation. 51 These data indicate that strategies aimed at inhibiting MBD2 should not raise the same concerns as anti-DNMT1 strategies with respect to possible increases in genomic instability and tumori genesis.…”

Section: Methyl-binding Domain Proteinmentioning

confidence: 96%

Mechanisms of Disease: methyl-binding domain proteins as potential therapeutic targets in cancer

2007

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The methyl-CpG-binding domain (MBD) proteins 'read' and interpret the methylation moieties on DNA, and thus are critical mediators of many epigenetic processes. Currently, the MBD family comprises five members; MBD1, MBD2, MBD3, MBD4 and MeCP2. Although not a 'classical' MBD protein, Kaiso also mediates transcriptional repression by using zinc finger domains to bind its targets. Since DNA hypermethylation is a well-recognized mechanism underlying gene silencing events in both tumorigenesis and drug resistance, it is likely that the MBD proteins may be important modulators of tumorigenesis. We review the recent work addressing this possibility, and discuss several of the MBD proteins as potentially excellent novel therapeutic targets.

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“…We can hypothesise that the absence of MBD2 produces a 'leak' in the CpG island hypermethylation silencing of tumour-suppressor genes, thereby partially aborting aberrant cancer growth. This may not be universal for all tumour types and in this regard deficiency of MBD2 does not enhance lymphomagenesis in p53-deficient mice (Sansom et al, 2005). Expression analysis of MBD proteins in tumours has revealed increased overall levels associated with enhanced proliferation (Esteller, 2005a).…”

Section: Estellermentioning

confidence: 99%

Epigenetics provides a new generation of oncogenes and tumour-suppressor genes

2006

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Cancer is nowadays recognised as a genetic and epigenetic disease. Much effort has been devoted in the last 30 years to the elucidation of the 'classical' oncogenes and tumour-suppressor genes involved in malignant cell transformation. However, since the acceptance that major disruption of DNA methylation, histone modification and chromatin compartments are a common hallmark of human cancer, epigenetics has come to the fore in cancer research. One piece is still missing from the story: are the epigenetic genes themselves driving forces on the road to tumorigenesis? We are in the early stages of finding the answer, and the data are beginning to appear: knockout mice defective in DNA methyltransferases, methyl-CpG-binding proteins and histone methyltransferases strongly affect the risk of cancer onset; somatic mutations, homozygous deletions and methylation-associated silencing of histone acetyltransferases, histone methyltransferases and chromatin remodelling factors are being found in human tumours; and the first cancer-prone families arising from germline mutations in epigenetic genes, such as hSNF5/INI1, have been described. Even more importantly, all these 'new' oncogenes and tumour-suppressor genes provide novel molecular targets for designed therapies, and the first DNA-demethylating agents and inhibitors of histone deacetylases are reaching the bedside of patients with haematological malignancies.

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MBD2 deficiency does not accelerate p53 mediated lymphomagenesis

Cited by 17 publications

References 13 publications

Cancer genetics: mouse models of intestinal cancer

Cancer genetics: mouse models of intestinal cancer

Mechanisms of Disease: methyl-binding domain proteins as potential therapeutic targets in cancer

Epigenetics provides a new generation of oncogenes and tumour-suppressor genes

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