Deletion of Mtgr1 Sensitizes the Colonic Epithelium to Dextran Sodium Sulfate–Induced Colitis

Martínez, J. A.; Williams, Christopher S.; Amann, Joseph M.; Ellis, Tiffany C.; Moreno–Miralles, Isabel; Washington, Mary Kay; Gregoli, Paul A.; Hiebert, Scott W.

doi:10.1053/j.gastro.2006.06.009

Cited by 27 publications

(31 citation statements)

References 24 publications

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“…In addition to the small intestinal phenotype, the colons of the Mtgr1-null mice were hypersensitive to the ulcerative agent dextran sodium sulfate (DSS). After treatment with DSS, the Mtgr1-null colonic epithelium failed to correctly regenerate, suggesting altered stem cell functions (38). Targeted gene disruption of Mtg8 indicated that it is required for development of the gut (7), but without defects in lineage contributions.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Mtg16, a Target of t(16;21), Alters Hematopoietic Progenitor Cell Proliferation and Lineage Allocation

Chyla¹,

Moreno–Miralles²,

Steapleton³

et al. 2008

Molecular and Cellular Biology

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Chromosomal translocations disrupt master regulatory genes that control cellular proliferation, apoptosis, and the lineage decisions of progenitor cells (25,53). Indeed, a critical component in the development of acute leukemia is the shunting of stem cells or multipotent progenitor cells toward a specific lineage, which also must acquire the ability to self-renew, to give rise to a specific form of acute myeloid leukemia (AML). The myeloid translocation gene on chromosome 16 (MTG16, also known as ETO-2 or CBFA2T3) and myeloid translocation gene on chromosome 8 (MTG8, also known as Eight-Twenty-one or ETO) are disrupted by t(16;21) and t(8;21), respectively. While t(8; 21) accounts for as much as 10 to 15% of de novo AML (11, 12, 16, 17, 30, 43, 44), t(16;21) is relatively rare. Yet, the analysis of genes involved in rare translocations is often highly informative (35). In addition to mutations in acute leukemia, MTG8 was identified as a candidate cancer gene in colorectal carcinoma and mutations in MTG16 were also found in the initial screen (59). Moreover, MTG16 may also be inactivated in breast cancer (31). Thus, the analysis of the normal physiological functions of the MTG family is critical to our understanding of the development of acute leukemia and how mutation of MTG family members contributes to tumorigenesis in other organ systems.The chromosomal translocation fusion proteins created at the breakpoints of t(8;21) and t(16;21) repress the transcription of tumor suppressor genes and genes that are required for hematopoietic differentiation (34). This is achieved by recruiting histone deacetylases and other transcriptional corepressors through their MTG8 or MTG16 sequences. Indeed, MTG family members associate with N-CoR/SMRT; mSin3A/3B; and histone deacetylases 1, 2, and 3 (2,18,23,36,63). MTG family members are recruited by DNA binding factors involved in chromosomal translocations (PLZF and BCL6) and by other regulators of hematopoiesis (e.g., TAL1/SCL, Gfi1, Gfi1b, and HEB) (9,20,39,40,55,68). Thus, the cumulative data suggest that the MTG/ETO family members function as transcriptional corepressors whose activities are coopted by chromosomal translocations to induce leukemia.Gene disruption strategies have been valuable to dissect the regulatory pathways and identify the critical factors that mediate the decision of a stem cell to self-renew and quiesce or to enter the rapidly expanding progenitor cell pool to populate the various hematopoietic cell lineages. Many of these key regulators are DNA binding transcription factors, which control gene expression programs to influence proliferation and differentiation. By contrast, only a limited number of the transcriptional regulators and chromatin remodeling factors that are recruited by DNA binding factors have been pinpointed as contributors to stem cell functions. This is especially true for transcriptional corepressors and gene silencing factors. Although a great deal of information has been gathered about the molecular interactions of the MTG famil...

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Section: Discussionmentioning

confidence: 99%

Deletion of Mtg16, a Target of t(16;21), Alters Hematopoietic Progenitor Cell Proliferation and Lineage Allocation

Chyla¹,

Moreno–Miralles²,

Steapleton³

et al. 2008

Molecular and Cellular Biology

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“…Furthermore, both Mtgr1 -/-and Mtg16 -/-mice have increased enterocyte proliferation with an expansion of transit-amplifying cell populations and skewed lineage allocation, indicative of disrupted intestinal homeostasis (12,15,16). When colitis was induced with dextran sodium sulfate (DSS), both Mtgr1 -/-and Mtg16 -/-mice were more sensitive to injury in comparison with wild-type (WT) mice, demonstrating that MTGs are required for maintaining intestinal integrity when the epithelium is challenged (10,13). Relevance to human disease is suspected, as UC patients have reductions in MTG16 expression (10).…”

Section: Mtg16mentioning

confidence: 99%

“…Glyceraldehyde 3-phosphate dehydrogenase (Gapdh)-specific primers and Wnt pathway primers (MWNT-I) were purchased from RealTimePrimers. Analysis was performed in triplicate as previously described (13). Fold-change was calculated using the delta-delta Ct method (39).…”

Section: Mtg16mentioning

confidence: 99%

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MTG16 is a tumor suppressor in colitis-associated carcinoma

Em¹,

Cw²,

Parang³

et al. 2017

JCI Insight

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“…The inactivation of Mtgr1 appeared to impair lineage allocation in the small intestine at the level of the secretory progenitor or through alterations in intestinal stem cell functions (1,32). In addition, loss of Mtgr1 sensitized the colonic epithelium to the effects of dextran sodium sulfate and impaired the regeneration of the colonic crypts, suggesting a role for Mtgr1 in the colonic stem cell (32).…”

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confidence: 99%

Myeloid Translocation Gene Family Members Associate with T-Cell Factors (TCFs) and Influence TCF-Dependent Transcription

Moore¹,

Amann²,

Williams

et al. 2008

Molecular and Cellular Biology

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Canonical Wnt signaling is mediated by a molecular "switch" that regulates the transcriptional properties of the T-cell factor (TCF) family of DNA-binding proteins. Members of the myeloid translocation gene (MTG) family of transcriptional corepressors are frequently disrupted by chromosomal translocations in acute myeloid leukemia, whereas MTG16 may be inactivated in up to 40% of breast cancer and MTG8 is a candidate cancer gene in colorectal carcinoma. Genetic studies imply that this corepressor family may function in stem cells. Given that mice lacking Myeloid Translocation Gene Related-1 (Mtgr1) fail to maintain the secretory lineage in the small intestine, we surveyed transcription factors that might recruit Mtgr1 in intestinal stem cells or progenitor cells and found that MTG family members associate specifically with TCF4. Coexpression of ␤-catenin disrupted the association between these corepressors and TCF4. Furthermore, when expressed in Xenopus embryos, MTG family members inhibited axis formation and impaired the ability of ␤-catenin and XLef-1 to induce axis duplication, indicating that MTG family members act downstream of ␤-catenin. Moreover, we found that c-Myc, a transcriptional target of the Wnt pathway, was overexpressed in the small intestines of mice lacking Mtgr1, thus linking inactivation of Mtgr1 to the activation of a potent oncogene.Canonical Wnt signaling plays a critical regulatory role in development and in stem cell functions and cellular differentiation (41, 43). Wnts initiate a signaling cascade that leads to the nuclear accumulation of ␤-catenin, which associates with T-cell factor 4 (TCF4), releasing the TCF4-associated transcriptional corepressors and recruiting coactivators to stimulate TCF4-dependent transcription. The intestinal epithelium has been a rich source of information about this pathway. For example, Tcf4 is required for small intestinal stem cell selfrenewal; mice lacking this transcription factor exhaust the capacity for continued replenishment of the epithelium in utero (24). Conversely, hyperactive Wnt signaling is closely associated with colorectal carcinoma, most commonly via inactivation of the APC tumor suppressor, which regulates the levels of ␤-catenin (41, 43). At the end point of the Wnt signaling cascade, ␤-catenin opposes the action of transcriptional corepressors for binding to TCFs to regulate genes that affect cell fate decisions.Two members of the myeloid translocation gene (MTG) family of transcriptional corepressors, MTG on chromosome 8 (MTG8; also known as ETO or RUNX1T1) and MTG on chromosome 16 (MTG16; also known as ETO2 or CBFA2T3), are disrupted by chromosomal translocations in acute myeloid leukemia (10, 29), which suggests that these factors are key regulators of cellular proliferation or differentiation. As would be expected of master regulatory factors, these targets of chromosomal translocations in acute leukemia are commonly mutated in other tumor types as well. A genomewide screen to detect mutations of genes in colorectal and breast can...

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Deletion of Mtgr1 Sensitizes the Colonic Epithelium to Dextran Sodium Sulfate–Induced Colitis

Cited by 27 publications

References 24 publications

Deletion of Mtg16, a Target of t(16;21), Alters Hematopoietic Progenitor Cell Proliferation and Lineage Allocation

Deletion of Mtg16, a Target of t(16;21), Alters Hematopoietic Progenitor Cell Proliferation and Lineage Allocation

MTG16 is a tumor suppressor in colitis-associated carcinoma

Myeloid Translocation Gene Family Members Associate with T-Cell Factors (TCFs) and Influence TCF-Dependent Transcription

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