title: Apoptosis induced by overall metabolic stress converges on the Bcl-2 family proteins Noxa and Mcl-1.
abstract: Apoptosis provoked by glucose shortage in dividing T cells is mediated via the BH3-only protein Noxa and inhibition of its binding partner Mcl-1. It is unknown how signals from cellular metabolism can affect the balance between Mcl-1 and Noxa and to what extent other Bcl-2 members are involved in this apoptosis cascade. Here, we defined the mechanism underlying apoptosis in relation to various types of metabolic stress. First, we established that the Noxa/Mcl-1 balance is regulated by glucose deprivation as well as by general metabolic stress, via changes in proteasome-mediated degradation of Mcl-1. Second, in contrast with cytokine-deprivation, no transcriptional modulation of Mcl-1, Puma, Bim or Noxa was observed during glucose deprivation. Third, no changes in PKB or GSK3 activity occurred and no clear role for AMPK was detected. Fourth, apoptosis triggered by nutrient deprivation was executed without signs of overt autophagy and independent of ROS production or p38 MAP kinase activity. Lastly, apoptosis under nutrient limitation could also be delayed by knock-down of Bim or overexpression of Bcl-2. In conclusion, Noxa functions in a specific apoptotic pathway that integrates overall nutrient stress, independent from attenuated PI3K/PKB signaling and without clear involvement of autophagy.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Felix M
authors.initials: FM
authors.lastname: Wensveen
authors.forename: Nuno L
authors.initials: NL
authors.lastname: Alves
authors.forename: Ingrid A M
authors.initials: IA
authors.lastname: Derks
authors.forename: Kris A
authors.initials: KA
authors.lastname: Reedquist
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D005947:Glucose / Q000172:deficiency; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D019289:Pyruvic Acid / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D019289:Pyruvic Acid; D011494:Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000091162:AMP-Activated Protein Kinase Kinases; D046988:Proteasome Endopeptidase Complex; D005947:Glucose