title: Recognition-dependent signaling events in response to apoptotic targets inhibit epithelial cell viability by multiple mechanisms: implications for non-immune tissue homeostasis.
abstract: Apoptosis allows for the removal of damaged, aged, and/or excess cells without harm to surrounding tissue. To accomplish this, cells undergoing apoptosis acquire new activities that enable them to modulate the fate and function of nearby cells. We have shown that receptor-mediated recognition of apoptotic versus necrotic target cells by viable kidney proximal tubular epithelial cells (PTEC) modulates the activity of several signaling pathways critically involved in regulation of proliferation and survival. Generally, apoptotic and necrotic targets have opposite effects with apoptotic targets inhibiting and necrotic targets stimulating the activity of these pathways. Here we explore the consequences of these signaling differences. We show that recognition of apoptotic targets induces a profound decrease in PTEC viability through increased responder cell death and decreased proliferation. In contrast, necrotic targets promote viability through decreased death and increased proliferation. Both target types mediate their effects through a network of Akt-dependent and -independent events. Apoptotic targets modulate Akt-dependent viability in part through a reduction in cellular β-catenin and decreased inactivation of Bad. In contrast, Akt-independent modulation of viability occurs through activation of caspase-8, suggesting that death receptor-dependent pathways are involved. Apoptotic targets also activate p38, which partially protects responders from target-induced death. The response of epithelial cells varies depending on their tissue origin. Some cell lines, like PTEC, demonstrate decreased viability, whereas others (e.g. breast-derived) show increased viability. By acting as sentinels of environmental change, apoptotic targets allow neighboring cells, especially non-migratory epithelial cells, to monitor and potentially adapt to local stresses.
authors.affiliation: Section of Nephrology, Department of Medicine, University of Illinois, Chicago, Illinois 60612, USA.
authors.forename: Vimal A
authors.initials: VA
authors.lastname: Patel
authors.forename: Lanfei
authors.initials: L
authors.lastname: Feng
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lee
authors.forename: Donald
authors.initials: D
authors.lastname: Massenburg
authors.forename: Goutham
authors.initials: G
authors.lastname: Pattabiraman
authors.forename: Angelika
authors.initials: A
authors.lastname: Antoni
authors.forename: John H
authors.initials: JH
authors.lastname: Schwartz
authors.forename: Wilfred
authors.initials: W
authors.lastname: Lieberthal
authors.forename: Joyce
authors.initials: J
authors.lastname: Rauch
authors.forename: David S
authors.initials: DS
authors.lastname: Ucker
authors.forename: Jerrold S
authors.initials: JS
authors.lastname: Levine
mesh_terms: D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D049109:Cell Proliferation; D002470:Cell Survival; D006224:Cricetinae; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D007107:Immune System; D007668:Kidney / Q000378:metabolism; D009336:Necrosis; D010586:Phagocytes / Q000166:cytology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases