MTG16 contributes to colonic epithelial integrity in experimental colitis

Williams, Christopher S.; Bradley, Amber; Chaturvedi, Rupesh; Singh, Kshipra; Piazuelo, M. Blanca; Chen, Xi; McDonough, Elizabeth; Schwartz, David L.; Brown, Caroline T.; Allaman, Margaret M.; Coburn, Lori A.; Horst, Sara; Beaulieu, Dawn B.; Choksi, Yash A.; Washington, Mary Kay; Williams, Amanda D.; Fisher, Melissa; Zinkel, Sandra S.; Peek, Richard M.; Wilson, Keith T.; Hiebert, Scott W.

doi:10.1136/gutjnl-2011-301439

Cited by 23 publications

(42 citation statements)

References 32 publications

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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%

“…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). In addition to their roles in healing and repair, multiple nonsynonymous MTG16 mutations have been identified in epithelial malignancies, including CRC (17).…”

Section: Mtg16mentioning

confidence: 99%

“…Upon sacrifice, tumors were quantified in a blinded fashion under stereo-dissecting microscopy. A histologic injury score was calculated and severity of dysplasia determined by an experienced GI pathologist (MKW) (10,21). All in vivo procedures were carried out in accordance with protocols approved by the Vanderbilt Institutional Animal Care and Use Committee.…”

Section: Mtg16mentioning

confidence: 99%

“…Recent work has implicated the myeloid translocation genes (MTGs) in intestinal inflammation, stem cell function, and epithelial repair -all processes contributing to the development of CAC (9)(10)(11)(12)(13). The MTG family includes MTG16 (CBFA2T3), MTGR1 (CBFA2T2), and MTG8 (RUNX1T1) (14).…”

Section: Introductionmentioning

confidence: 99%

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MTG16 is a tumor suppressor in colitis-associated carcinoma

Em¹,

Cw²,

Parang³

et al. 2017

JCI Insight

Self Cite

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Section: Mtg16mentioning

confidence: 99%

Section: Mtg16mentioning

confidence: 99%

Section: Mtg16mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MTG16 is a tumor suppressor in colitis-associated carcinoma

Em¹,

Cw²,

Parang³

et al. 2017

JCI Insight

Self Cite

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“…These models are useful to explore pathways or therapeutics that are thought to protect intestinal epithelial cells from damage or stress response as well as pathways that maintain gut integrity in the presence of a biological insult. Animals that have genetic deficiencies in permeability through a variety of mechanisms (Laukoetter et al 2007;Kong et al 2008;Chogle et al 2011;Williams et al 2012) have been shown to be more susceptible to DSS colitis. Consistent with this, therapeutics that maintain or increase gut permeability are protective in DSS colitis (Ukena, Singh, and Westendorf 2007;Chogle et al 2011).…”

Section: Considerations For Choosing a Preclinical Modelmentioning

confidence: 99%

Murine Models of Inflammatory Bowel Disease (IBD)

DeVoss¹,

Diehl²

2013

Toxicol Pathol

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Animal models of human disease are a critical tool in both basic research and drug development. The results of preclinical efficacy studies often inform progression of therapeutic candidates through the drug development pipeline; however, the extent to which results in inflammatory bowel disease (IBD) models predict human drug response is an ongoing concern. This review discusses how murine models are currently being used in IBD research. We focus on the considerations and caveats for commonly used models in preclinical efficacy studies and discuss the value of models that utilize specific pathogenic pathways of interest rather than model all aspects of human disease.

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Loss of PHLPP protects against colitis by inhibiting intestinal epithelial cell apoptosis

Wen

Goretsky

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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A common feature of inflammatory bowel disease (IBD) is the loss of intestinal epithelial barrier function due to excessive apoptosis of intestinal epithelial cells (IECs). However, the molecular mechanism underlying increased IEC apoptosis remains unclear. Here, we investigated the role of PHLPP, a novel family of protein phosphatates, in regulating inflammation-induced IEC apoptosis in mouse models of colitis. Both Phlpp1 and Phlpp2 genes were deleted in mice. Compared with wild-type mice, PHLPP double knockout (DKO) mice were protected from colitis induced by DSS as demonstrated by lower histopathological scores, and this reduced susceptibility to colitis was associated with decreased apoptosis and increased Akt activity in IECs in vivo. In addition, epithelial organoids derived from PHLPP DKO mice were more resistant to inflammation-induced apoptosis while inhibition of Akt activity abolished the protective effect of PHLPP-loss. Furthermore, we found that PHLPP expression was significantly reduced in IECs following the induction of colitis by DSS and in human IBD patient samples. This inflammation-induced downregulation of PHLPP was partially blocked by treating cells with a proteasome inhibitor. Taken together, our results indicated that proteasome-mediated degradation of PHLPP at the onset of inflammation plays an important role in protecting IEC injury by inhibiting apoptosis.

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MTG16 contributes to colonic epithelial integrity in experimental colitis

Cited by 23 publications

References 32 publications

MTG16 is a tumor suppressor in colitis-associated carcinoma

MTG16 is a tumor suppressor in colitis-associated carcinoma

Murine Models of Inflammatory Bowel Disease (IBD)

Loss of PHLPP protects against colitis by inhibiting intestinal epithelial cell apoptosis

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