title: Apoptotic cells activate AMP-activated protein kinase (AMPK) and inhibit epithelial cell growth without change in intracellular energy stores.
abstract: Apoptosis plays an indispensable role in the maintenance and development of tissues. We have shown that receptor-mediated recognition of apoptotic target cells by viable kidney proximal tubular epithelial cells (PTECs) inhibits the proliferation and survival of PTECs. Here, we examined the effect of apoptotic targets on PTEC cell growth (cell size during G1 phase of the cell cycle). Using a cell culture model, we show that apoptotic cells potently activate AMP-activated protein kinase (AMPK), a highly sensitive sensor of intracellular energy stores. AMPK activation leads to decreased activity of its downstream target, ribosomal protein p70 S6 kinase (p70S6K), and concomitant inhibition of cell growth. Importantly, these events occur without detectable change in intracellular levels of AMP, ADP, or ATP. Inhibition of AMPK, either pharmacologically by compound C or molecularly by shRNA, diminishes the effects of apoptotic targets and largely restores p70S6K activity and cell size to normal levels. Apoptotic targets also inhibit Akt, a second signaling pathway regulating cell growth. Expression of a constitutively active Akt construct partially relieved cell growth inhibition but was less effective than inhibition of AMPK. Inhibition of cell growth by apoptotic targets is dependent on physical interaction between apoptotic targets and PTECs but independent of phagocytosis. We conclude that receptor-mediated recognition of apoptotic targets mimics the effects of intracellular energy depletion, activating AMPK and inhibiting cell growth. By acting as sentinels of environmental change, apoptotic death may enable nearby viable cells, especially nonmigratory epithelial cells, to monitor and adapt to local stresses.
authors.affiliation: From the Section of Nephrology, Departments of Medicine and the Section of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Hospital, Chicago, Illinois 60612.
authors.forename: Vimal A
authors.initials: VA
authors.lastname: Patel
authors.affiliation: From the Section of Nephrology, Departments of Medicine and the Section of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Hospital, Chicago, Illinois 60612.
authors.forename: Donald
authors.initials: D
authors.lastname: Massenburg
authors.affiliation: From the Section of Nephrology, Departments of Medicine and the Section of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Hospital, Chicago, Illinois 60612.
authors.forename: Snezana
authors.initials: S
authors.lastname: Vujicic
authors.affiliation: From the Section of Nephrology, Departments of Medicine and the Section of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Hospital, Chicago, Illinois 60612.
authors.forename: Lanfei
authors.initials: L
authors.lastname: Feng
authors.affiliation: the Section of Nephrology, Department of Medicine, Stony Brook University Medical Center, Stony Brook, New York 11794, the Northport Veterans Affairs Hospital, Northport, New York 11768.
authors.forename: Meiyi
authors.initials: M
authors.lastname: Tang
authors.affiliation: From the Section of Nephrology, Departments of Medicine and the Section of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Hospital, Chicago, Illinois 60612.
authors.forename: Natalia
authors.initials: N
authors.lastname: Litbarg
authors.affiliation: the Department of Biology, Kutztown University of Pennsylvania, Kutztown, Pennsylvania 19530, and.
authors.forename: Angelika
authors.initials: A
authors.lastname: Antoni
authors.affiliation: the Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Joyce
authors.initials: J
authors.lastname: Rauch
authors.affiliation: the Section of Nephrology, Department of Medicine, Stony Brook University Medical Center, Stony Brook, New York 11794, the Northport Veterans Affairs Hospital, Northport, New York 11768.
authors.forename: Wilfred
authors.initials: W
authors.lastname: Lieberthal
authors.affiliation: From the Section of Nephrology, Departments of Medicine and the Section of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Hospital, Chicago, Illinois 60612, Microbiology and Immunology, University of Illinois, Chicago, Illinois 60612, jslevine@uic.edu.
authors.forename: Jerrold S
authors.initials: JS
authors.lastname: Levine
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000227:Adenine Nucleotides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000227:Adenine Nucleotides; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D055372:AMP-Activated Protein Kinases
keywords: ADP; AMP; AMP-activated kinase (AMPK); ATP; Akt PKB; apoptosis; cell growth; epithelial cell; innate immunity; kidney