Deficiency of Mbd2 suppresses intestinal tumorigenesis

Sansom, Owen J.; Berger, Jennifer; Bishop, Stefan Mark; Hendrich, Brian; Bird, Adrian; Clarke, Alan R.

doi:10.1038/ng1155

Cited by 165 publications

(146 citation statements)

References 11 publications

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“…On the other hand, introduction of Mbd2 homozygous mutation in Apc Min mice also reduced the polyp numbers to B1/10. As Mbd2 encodes methyl-CpG binding repressor that recruits corepressor complexes to methylated DNA, these results indicate that DNA methylation-mediated gene silencing is integral to the Apc Min polyposis (Sansom et al, 2003).…”

Section: Modifier Genes Of Apc Intestinal Polyposismentioning

confidence: 90%

Wnt signaling and gastrointestinal tumorigenesis in mouse models

Taketo

2006

Oncogene

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The canonical Wnt signaling plays important roles in embryonic development and tumorigenesis. For the latter, induced mutations in mice have greatly contributed to our understanding of the molecular mechanisms of cancer initiation and progression. Here, I will review recent reports on gastrointestinal cancer model mice, with an emphasis on the roles of the Wnt signal pathway. They include: mouse models for familial adenomatous polyposis; modifying factors that affect mouse intestinal polyposis, including the genes that help cancer progression; Wnt target genes that affect mouse intestinal polyposis; and a mouse model of gastric cancer that mimics Helicobacter pyroli infection.

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Section: Modifier Genes Of Apc Intestinal Polyposismentioning

confidence: 90%

Wnt signaling and gastrointestinal tumorigenesis in mouse models

Taketo

2006

Oncogene

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“…Also, Mbd2 deficiency does not predispose to tumor formation. On the contrary, when bred onto a bona fide model for intestinal cancer, the Apc min mouse, loss of Mbd2 significantly delays tumorigenesis (Sansom et al 2003). Furthermore, MBD2 knockdown in human cancer cell lines was found to suppress tumorigenesis in a mouse xenograft model (Ivanov et al 2003;Campbell et al 2004).…”

Section: Methyl-dna-binding Proteinsmentioning

confidence: 99%

Epigenetics and cancer

Lund¹,

Lohuizen²

2004

Genes Dev.

442

318

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Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation locally and globally via modifications of the DNA and by modification or rearrangement of nucleosomes. Epigenetic gene regulation collaborates with genetic alterations in cancer development. This is evident from every aspect of tumor biology including cell growth and differentiation, cell cycle control, DNA repair, angiogenesis, migration, and evasion of host immunosurveillance. In contrast to genetic cancer causes, the possibility of reversing epigenetic codes may provide new targets for therapeutic intervention.Epigenetic programming is crucial in mammalian development, and stable inheritance of epigenetic settings is essential for the maintenance of tissue-and cell-typespecific functions (Li 2002). With the exception of controlled genomic rearrangements, such as those of the immunoglobulin and T-cell receptor genes in B and T cells, all other differentiation processes are initiated or maintained through epigenetic processes. Not surprisingly therefore, epigenetic gene regulation is characterized overall by a high degree of integrity and stability. Evidence is accumulating that suggests that the intrinsic stability is caused by multiple interlocking feedback mechanisms between functionally unrelated epigenetic layers, such as DNA methyltransferases (DNMTs) and histone modifying enzymes, resulting in the stable commitment of a locus to a particular activity state. In somatic cells, the transcriptional status of most genes is epigenetically fixed. However, other genes, such as cell cycle checkpoint genes and genes directly affected by exogenous stimuli such as growth factors or cell-cell contact, likely reside in a balanced state sensitive to dynamic adjustments in histone modifications, thereby allowing for rapid responses to specific stimuli. Perturbation of epigenetic balances may lead to alterations in gene expression, ultimately resulting in cellular transformation and malignant outgrowth; the involvement of deregulated epigenetic mechanisms in cancer development has received increased attention in recent years.Per definition, epigenetic regulators alter the activities and abilities of a cell without directly affecting and mutating the sequence of the DNA. In this review, we deal with epigenetic gene regulation as imposed by DNA methylation, covalent modifications of the canonical core histones, deposition of variant histone proteins, local nucleosome remodeling, and long-range epigenetic regulators. Understanding the molecular details behind "epigenetic cancer diseases" holds potentially important prospects for medical treatment, as it allows for novel strategies for drug development. A number of recent reviews have provided details on epigenetic mechanisms and their involvement in cancer, and we refer to these for more in-depth information on individual epigenetic mechanisms

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“…However, deficiency of MBD2 suppresses intestinal tumorigenesis in an Mbd2-knockout mouse derived from a lineage with an autosomal-dominantly inherited predisposition to multiple intestinal neoplasia (Min) (Sansom et al, 2003). 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.…”

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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Deficiency of Mbd2 suppresses intestinal tumorigenesis

Cited by 165 publications

References 11 publications

Wnt signaling and gastrointestinal tumorigenesis in mouse models

Wnt signaling and gastrointestinal tumorigenesis in mouse models

Epigenetics and cancer

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

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