p38 MAPK regulates Bax activity and apoptosis in enterocytes at baseline and after intestinal resection

Wakeman, Derek; Guo, Jun; Santos, Jethrina A.; Wandu, Wambui S.; Schneider, John E.; McMellen, Mark E.; Leinicke, Jennifer A.; Erwin, Christopher R.; Warner, Brad W.

doi:10.1152/ajpgi.00485.2011

Cited by 26 publications

(25 citation statements)

References 46 publications

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“…Our lab has recently developed an inducible, enterocyte-specific p38-alpha-deleted mouse model 22 . We have found that p38 MAPK is efficiently deleted in all enterocytes including the colonic epithelium.…”

Section: Introductionmentioning

confidence: 99%

“…Our findings in mice with enterocyte-specific p38 deletion are consistent with its role as a tumor suppressor. Mice that lack p38 display increased proliferation and decreased apoptosis in the crypt cells of the small intestine 22 . Our results mirror work recently published by Otsuka et al who found that a constitutive, intestine-specific deletion of p38 led to a hyperproliferative state in the crypt compartment 24 .…”

Section: Introductionmentioning

confidence: 99%

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Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis

Wakeman¹,

Schneider²,

Liu³

et al. 2012

Surgery

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Background p38-alpha MAPK (p38) is a tumor suppressor often mutated in human cancers, but its specific role in colorectal cancer is not completely understood. Prior studies have found that p38 activity inhibits epithelial proliferation and promotes apoptosis in the intestine. Therefore, we sought to test the hypothesis that intestinal disruption of p38 would lead to increased tumorigenesis in the colon. Methods p38 was deleted in mice within the intestinal epithelium using a tamoxifen-inducible Cre system under control of the villin promoter [villin-Cre ERT2(+), MAPK14(f/f)]. An azoxymethane (AOM) and dextran sodium sulfate (DSS) protocol was used to drive intestinal tumor development. Tumor measurements were made using computer software from photographs of excised colon specimens. Results The number of mice that developed tumors was not statistically different when comparing wild type (WT) mice (7 of 14) to inducible, intestine epithelial-deleted p38 (ed-p38, 9 of 11) mice after AOM/DSS treatment (p=0.21). However, the ed-p38 mice developed significantly more tumors (3.7 vs 1.1, p=0.008) and nearly four-times the total tumor burden as WT mice (17.4 vs 4.8 mm2, p=0.03). WT and ed-p38 groups demonstrated a similar degree of colon inflammation. Conclusions Deletion of p38-alpha MAPK within the colonic mucosa leads to a hyperplastic state promoting greater tumor development. Since the severity of colitis was not augmented in mice with p38 deficiency, tumor development is likely mediated by impaired cell cycle regulation within the colonic epithelium. Manipulation of p38 activity may provide a novel treatment and/or prevention strategy in the management of colorectal cancer, particularly in the setting of inflammatory bowel disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis

Wakeman¹,

Schneider²,

Liu³

et al. 2012

Surgery

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“…H&E stained slides were analyzed for apoptotic bodies (pyknotic nuclei, condensed chromatin, and nuclear fragmentation) [18]. An apoptosis index was determined by counting the number apoptotic bodies found within 50 well-oriented crypts.…”

Section: Methodsmentioning

confidence: 99%

Both epidermal growth factor and insulin-like growth factor receptors are dispensable for structural intestinal adaptation

Sun

Diaz-Miron

Choi

et al. 2015

Journal of Pediatric Surgery

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Purpose Intestinal adaptation structurally represents increases in crypt depth and villus height in response to small bowel resection (SBR). Previously, we found that neither epidermal growth factor receptor (EGFR) nor insulin-like growth factor 1 receptor (IGF1R) function was individually required for normal adaptation. In this study, we sought to determine the effect of disrupting both EGFR and IGF1R expression on resection-induced adaptation. Methods Intestinal-specific EGFR and IGF1R double knockout mice (EGFR/IGF1R-IKO) (n=6) and wild-type (WT) control mice (n=7) underwent 50% proximal SBR. On postoperative day (POD) 7, structural adaptation was scored by measuring crypt depth and villus height. Rates of crypt cell proliferation, apoptosis, and submucosal capillary density were also compared. Results After 50% SBR, normal adaptation occurred in both WT and EGFR/IGF1R-IKO. Rates of proliferation and apoptosis were no different between the two groups. The angiogenic response was less in the EGFR/IGF1R-IKO compared to WT mice. Conclusion Disrupted expression of EGFR and IGF1R in the intestinal epithelial cells does not affect resection-induced structural adaptation but attenuates angiogenesis after SBR. These findings suggest that villus growth is driven by receptors and pathways that occur outside the epithelial cell component, while angiogenic responses may be influenced by epithelial-endothelial crosstalk.

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“…Each postoperative H&E stained sections were analyzed for apoptotic bodies (pyknotic nuclei, condensed chromatin) [14]. An apoptosis index was measured by counting the number apoptotic bodies found per 50 crypts.…”

Section: Methodsmentioning

confidence: 99%

Insulin-like growth factor 2 and its enterocyte receptor are not required for adaptation in response to massive small bowel resection

Sun

Choi

Guo

et al. 2014

Journal of Pediatric Surgery

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Purpose Enhanced structural features of resection-induced intestinal adaptation have been demonstrated following the administration of multiple different growth factors and peptides. Among these, the insulin-like growth factor (IGF) system has been considered to be significant. In this study, we employ mutant mouse strains to directly test the contribution of IGF2 and its enterocyte receptor (IGF1R) toward the adaptation response to massive small bowel resection (SBR). Methods IGF2-knockout (IGF2-KO) (n=8) and intestine specific IGF1R-knockout mice (IGF1R-IKO) (n=9) and their wild type (WT) littermates (n=5, n=7, respectively) underwent 50% proximal SBR. At post-operative day 7, structural adaptation was measured as crypt depth and villus height. Rates of enterocyte proliferation and apoptosis were also recorded. Results The successful deletion of IGF2 and IGF1R expression in the enterocytes was confirmed by RT-PCR and Western blot, respectively. Normal adaptation occurred in both IGF2-KO and IGF1R-IKO mice after 50% SBR. Post-operative rates of proliferation and apoptosis in both IGF2-KO and IGF1R-IKO mice were no different than their respective controls. Conclusion IGF2 and functional IGF1R signaling in enterocytes are both dispensable for resection-induced adaptation responses. The mechanism for IGF-stimulation of intestinal adaptation may involve other ligands or cellular compartments within the intestine.

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p38 MAPK regulates Bax activity and apoptosis in enterocytes at baseline and after intestinal resection

Cited by 26 publications

References 46 publications

Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis

Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis

Both epidermal growth factor and insulin-like growth factor receptors are dispensable for structural intestinal adaptation

Insulin-like growth factor 2 and its enterocyte receptor are not required for adaptation in response to massive small bowel resection

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