Growth factor regulation of autophagy and cell survival in the absence of apoptosis.
In animals, cells are dependent on extracellular signals to prevent apoptosis. However, using growth factor-dependent cells from Bax/Bak-deficient mice, we demonstrate that apoptosis is not essential to limit cell autonomous survival. Following growth factor withdrawal, Bax-/-Bak-/- cells activate autophagy, undergo progressive atrophy, and ultimately succumb to death. These effects result from loss of the ability to take up sufficient nutrients to maintain cellular bioenergetics. Despite abundant extracellular nutrients, growth factor-deprived cells maintain ATP production from catabolism of intracellular substrates through autophagy. Autophagy is essential for maintaining cell survival following growth factor withdrawal and can sustain viability for several weeks. During this time, cells respond to growth factor readdition by rapid restoration of the ability to take up and metabolize glucose and by subsequent recovery of their original size and proliferative potential. Thus, growth factor signal transduction is required to direct the utilization of sufficient exogenous nutrients to maintain cell viability.
Lum
Julian J
JJ
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Bauer
Daniel E
DE
Kong
Mei
M
Harris
Marian H
MH
Li
Chi
C
Lindsten
Tullia
T
Thompson
Craig B
CB
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000648:ultrastructure; D053938:DNA Fragmentation / Q000502:physiology; D006019:Glycolysis / Q000502:physiology; D006133:Growth Substances / Q000172:deficiency*; D007377:Interleukin-3 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D006133:Growth Substances; D007377:Interleukin-3; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein