title: The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells.
abstract: Throughout lymphocyte development, cellular persistence and expansion are tightly regulated by survival and apoptosis. Within the Bcl-2 family, distinct apoptogenic BH3-only members like Bid, Bim, and Puma appear to function in specific cell death pathways. We found that naive human T cells after mitogenic activation, apart from expected protective Bcl-2 members, also rapidly upregulate the BH3-only protein Noxa in a p53-independent fashion. The specific role of Noxa became apparent during glucose limitation and involves interaction with the labile Bcl-2 homolog Mcl-1. Knockdown of Noxa or Mcl-1 results in protection or susceptibility, respectively, to apoptosis induced by glucose deprivation. Declining Mcl-1 levels and apoptosis induction are inversely correlated to Noxa levels and prevented by readdition of glucose. We propose that the Noxa/Mcl-1 axis is an apoptosis rheostat in dividing cells, in a selective pathway that functions to restrain lymphocyte expansion and can be triggered by glucose deprivation.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands.
authors.forename: Nuno L
authors.initials: NL
authors.lastname: Alves
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands.
authors.forename: Ingrid A M
authors.initials: IAM
authors.lastname: Derks
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Berk
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands; Department of Hematology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Spijker
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands.
authors.forename: René A W
authors.initials: RAW
authors.lastname: van Lier
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands. Electronic address: e.eldering@amc.uva.nl.
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
mesh_terms: D017209:Apoptosis / Q000235:genetics; D018106:CD28 Antigens / Q000494:pharmacology; D002455:Cell Division; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000819:agonists; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53; D011493:Protein Kinase C; D005947:Glucose