Fas Ag-FasL coupling leads to ERK1/2-mediated proliferation of gastric mucosal cells
Department of Medicine, Division of Gastroenterology
Animals; Antigens, CD95; Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; *Cell Proliferation; Cell Transformation, Neoplastic; Death Domain Receptor Signaling Adaptor Proteins; Epithelial Cells; Fas Ligand Protein; Gastric Mucosa; Humans; MAP Kinase Kinase Kinases; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Phosphorylation; Rats; Recombinant Fusion Proteins; Signal Transduction; Time Factors; Transfection
Life Sciences | Medicine and Health Sciences
When cells within the gastric mucosa progress from metaplasia to dysplasia to cancer, they acquire a Fas Ag apoptosis-resistant phenotype. It is unusual to completely abolish the pathway, suggesting other forms of Fas Ag signaling may be important or even necessary for gastric cancer to progress. Little is known about alternate signaling of the Fas Ag pathway in gastric mucosal cells. Using a cell culture model of rat gastric mucosal cells, we show that gastric mucosal cells utilize a type II signaling pathway for apoptosis. Under conditions of low receptor stimulation or under conditions where apoptosis is blocked downstream of the death-inducing signal complex, Fas Ag signaling proceeds toward proliferative signaling. Under conditions favoring proliferative signaling, cFLIP is recruited to the Fas-associated death domain-like interleukin-1beta-converting enzyme at the death-inducing signal complex and activates ERK1/2. ERK1/2 in turn activates NF-kappaB. ERK1/2 stimulates proliferation, whereas NF-kappaB activation results in upregulation of the antiapoptotic protein survivin, further promoting proliferation over apoptosis. These results suggest that factors that inhibit apoptosis confer a growth advantage to the cells beyond the survival advantage of avoiding apoptosis and in effect convert the Fas Ag signaling pathway from a tumor suppressor to a tumor promoter.
DOI of Published Version
2007 Nov 8. Link to article on publisher's site
American journal of physiology. Gastrointestinal and liver physiology
Li, Hanchen; Cai, Xun; Fan, Xueli; Moquin, Brian; Stoicov, Calin; and Houghton, JeanMarie, "Fas Ag-FasL coupling leads to ERK1/2-mediated proliferation of gastric mucosal cells" (2007). Open Access Articles. 1968.