Epidermal growth factor receptor signaling modulates apoptosis via p38alpha MAPK-dependent activation of Bax in intestinal epithelial cells.
Previous studies have demonstrated that the proapoptotic protein Bax plays an important role in the elevated enterocyte apoptosis that occurs during the intestinal adaptation response to massive small bowel resection (SBR). Additionally, epidermal growth factor receptor (EGFR) activation prevents SBR-induced enterocyte apoptosis. The present study aims to delineate the relationship between EGFR activity and intestinal epithelial cell apoptosis. Treatment of model intestinal epithelial cells (RIEC-18) with both a selective EGFR inhibitor (ZD1839) and EGFR small interfering RNA knockdown resulted in a dramatic increase in apoptosis, accompanied by rapid phosphorylation of p38alpha. Concurrently, Bax underwent conformational changes consistent with activation and translocated to mitochondria. In contrast, EGF stimulation enhanced cell survival by attenuating p38alpha phosphorylation, Bax conformational change, mitochondrial trafficking, and apoptosis. These results demonstrate that that diminished EGFR activity initiates the intrinsic pathway of apoptosis through p38alpha-dependent Bax activation in intestinal epithelial cells. These finding provide mechanistic insight into the role that EGFR signaling plays in the regulation of enterocyte apoptosis following massive intestinal loss.
Sheng
George
G
Division of Pediatric Surgery, St. Louis Children's Hospital, One Children's Place, St. Louis, MO 63110, USA.
Guo
Jun
J
Warner
Brad W
BW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D020895:Enterocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077156:Gefitinib; D007082:Ileum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
C494828:Bax protein, rat; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; D034741:RNA, Small Interfering; D020032:Tyrphostins; D051028:bcl-2-Associated X Protein; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048308:Mitogen-Activated Protein Kinase 14; C093642:SB 203580; D000077156:Gefitinib