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EGF receptor signaling affects bcl-2 family gene expression and apoptosis after massive small bowel resection
Andrew W Knott1, Russell J Juno, Marcus D Jarboe
1Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Background:
After massive small bowel resection (SBR), enterocyte apoptosis is elevated and inversely correlates with epidermal growth factor receptor (EGFR) signaling. The purpose of the current study was to determine whether EGFR manipulation affects the expression of specific bcl-2 family members.
Methods:
A 50% proximal SBR or sham operation was performed in 3 groups of mice control, after exogenous EGF, or mutant mice with defective EGFR signaling (waved-2). Apoptotic index (no. of apoptotic bodies per crypt), and bax (pro-apoptosis) and bcl-w (anti-apoptosis) protein expression was measured in the remnant ileum after 12, 24, and 72 hours.
Results:
Waved-2 mice with defective EGFR showed the greatest increase in apoptosis and altered the ratio of bax to bcl-w in favor of apoptosis after SBR. Conversely, EGF prevented the expected increase in apoptosis after SBR by shifting the ratio of bax to bcl-w in favor of cell survival.
Conclusions:
After massive small bowel resection, inhibition of the EGFR accelerates the rate of apoptosis and modifies the expression of specific bcl-2 family members to favor apoptosis. These results further support a specific mechanistic pathway for the regulation of enterocyte apoptosis after SBR via EGFR signaling.
Insights
Epidermal growth factor receptor (EGFR) signaling regulates enterocyte apoptosis after small bowel resection (SBR). Inhibiting EGFR accelerates apoptosis, while EGF promotes cell survival by altering bcl-2 family member expression.
Area of Science:
- Gastroenterology
- Cell Biology
- Molecular Biology
Background:
- Massive small bowel resection (SBR) increases enterocyte apoptosis.
- Epidermal growth factor receptor (EGFR) signaling is inversely correlated with enterocyte apoptosis post-SBR.
Purpose of the Study:
- To investigate how EGFR manipulation impacts bcl-2 family member expression in the context of SBR.
Main Methods:
- Mice underwent 50% proximal SBR or sham operation.
- Groups included control, exogenous EGF administration, and waved-2 mutant mice with defective EGFR signaling.
- Apoptotic index and bax/bcl-w protein expression were assessed in the ileum.
Main Results:
- Defective EGFR signaling in waved-2 mice significantly increased apoptosis post-SBR.
- EGFR inhibition accelerated apoptosis and favored pro-apoptotic bcl-2 family members.
- Exogenous EGF administration reduced apoptosis post-SBR by promoting cell survival.
Conclusions:
- EGFR signaling critically regulates enterocyte apoptosis following SBR.
- EGFR inhibition promotes apoptosis by altering bcl-2 family member expression.
- Targeting EGFR may offer therapeutic strategies for managing SBR-induced enterocyte apoptosis.