Society of University SurgeonsDeletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis
Section snippets
Animals
The protocol for this study was approved by the Washington University Institutional Animal Care and Use Committee (protocols #20070145 and #20100103; Washington University School of Medicine). All mice were bred and housed in a standard vivarium with a 12-hour day-night cycle. Inducible, intestine epithelial-deleted p38-alpha mice (ed-p38 mice) were generated by crossing mice with a tamoxifen-inducible Cre-fusion protein under control of the villin promoter (donated by Sylvie Robine, PhD, Curie
Efficiency of p38 deletion
Attenuated expression of p38 protein after tamoxifen injection was confirmed in the small intestine epithelium of all mice by Western immunoblotting after 77 days (Fig 2, A). Earlier time points after tamoxifen (7 days) revealed more efficient knockout of p38 protein expression in both intestinal epithelial cells and colon (Fig 2, B).
Weight change
As expected, both WT and ed-p38 mice lost weight compared to control mice given water during treatment with DSS (P < .05). However, the change in weight during the
Discussion
In the present study, we show that p38 deletion increases colon tumorigenesis after exposure to a potent carcinogen in the setting of a chronic inflammatory state. Mice with inducible, enterocyte-specific deletion of p38 MAPK developed more tumors and had a greater tumor burden than WT controls. These data suggest that under normal physiologic conditions, p38 MAPK serves as an important cell cycle inhibitor. Overall, our findings support the hypothesis that p38 MAPK may be an important
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Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis
2020, Cell MetabolismCitation Excerpt :However, FoxO factors have been involved in multiple cellular processes that potentially interact with mitochondrial function, most notably oxidative stress and redox homeostasis (Essers et al., 2004; van Doeselaar and Burgering, 2018). In fact, the oxidative stress-responsive MAPK p38 has been reported by us and others to be required for intestinal homeostasis (Houde et al., 2001; Rodríguez-Colman et al., 2017; Wakeman et al., 2012). Thus, in addition to mitochondrial fission, p38 could be involved in secretory differentiation upon Foxo KD.
Plakophilin3 loss leads to an increase in lipocalin2 expression, which is required for tumour formation
2018, Experimental Cell ResearchCitation Excerpt :Our results demonstrate that p38α and p38β might play opposing roles in regulating LCN2 expression and the balance between the activities of these two isoforms may be one of the mechanisms by which p38 MAPKs regulate tumour progression. In agreement with this hypothesis, p38α functions as a tumour suppressor role in colon cancers [60] and knocking down p38α increases tumour formation in axoxymethane (AOM)-DSS induced inflammation associated colon cancers [61]. These results are consistent with our observations that p38α might inhibit the transcription of LCN2.
Vacuolar protein sorting 4B regulates apoptosis of intestinal epithelial cells via p38 MAPK in Crohn's disease
2015, Experimental and Molecular PathologyCitation Excerpt :Intestinal epithelial cell-specific deletion of p38α disrupted intestinal epithelial homeostasis and increased progression of colitis in mice (Otsuka et al., 2010). Most studies have been concerning that p38 activity inhibits epithelial proliferation and promotes apoptosis in the intestine (Wakeman et al., 2012). The activation of EGFR initiates the intrinsic pathway of apoptosis via p38α-dependent Bax activation in intestinal epithelial cells (Sheng et al., 2007).
Mnk2 Alternative Splicing Modulates the p38-MAPK Pathway and Impacts Ras-Induced Transformation
2014, Cell ReportsCitation Excerpt :The role of the tumor suppressor activity of p38α was recently demonstrated in hepatocellular carcinoma and colon cancer development. In both cases, tissue-specific knockout of p38α led to cancer development in vivo (Sakurai et al., 2013) (Wakeman et al., 2012). Moreover, a recent study showed that the gene encoding MKK3, a known p38-MAPK upstream kinase, is lost in some breast tumors and that MKK3 acts as a tumor suppressor in breast cancer (MacNeil et al., 2014).
Fibrates Affect Levels of Phosphorylated p38 in Intestinal Cells in a Differentiation-Dependent Manner
2023, International Journal of Molecular SciencesIsoform-specific and cell/tissue-dependent effects of p38 MAPKs in regulating inflammation and inflammation-associated oncogenesis
2022, Frontiers in Bioscience - Landmark
Supported by National Institutes of Health Grants T32 CA009621 (Dr Wakeman), R01 DK059288 (Drs Wandu, Erwin, Guo, and Warner), R01 AI084887 (Dr Stappenbeck), P30 CA91842 (Dr Liu), and P30 DK52574 (Morphology and Murine Models Cores of the Digestive Diseases Research Core Center of the Washington University School of Medicine). Additional support was obtained from the Summer Undergraduate Research Fellowship (SURF) Program at Washington University (Mr Schneider) and the St Louis Children's Hospital Foundation–Children's Surgical Sciences Institute at Washington University School of Medicine.