title: Subcellular localization of PUMA regulates its pro-apoptotic activity in Burkitt's lymphoma B cells.
abstract: The BH3-only protein PUMA (p53-upregulated modulator of apoptosis) is a major regulator of apoptosis. It belongs to the Bcl-2 family of proteins responsible for maintaining mitochondrial outer membrane integrity by controlling the intrinsic (mitochondrial) apoptotic pathway. We describe here a new pathway regulating PUMA activation through the control of its subcellular distribution. Surprisingly, neither PUMA upregulation in normal activated human B lymphocytes nor high levels of PUMA in Burkitt's lymphoma (BL) were associated with cell death. We show that PUMA is localized to the cytosol in these cells. By contrast, various apoptosis-triggering signals were found to promote the translocation of PUMA to the mitochondria in these cells, leading to their death by apoptosis. This apoptosis was associated with the binding of mitochondrial PUMA to anti-apoptotic members of the Bcl-2 family, such as Bcl-2 and Mcl-1. This translocation was caspase-independent but was prevented by inhibiting or knocking down the expression of the MAPK kinase p38. Our data suggest that the accumulation of PUMA in the cytosol may be important for the participation of this protein in apoptosis without the need for prior transcription. This regulatory pathway may be an important feature of differentiation and tumorigenic processes.
authors.affiliation: INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France.|Université Paris-Saclay, France.|Equipe Labellisée Ligue contre le Cancer, Villejuif, France.
authors.forename: Gorbatchev
authors.initials: G
authors.lastname: Ambroise
authors.affiliation: INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France.|Université Paris-Saclay, France.|Equipe Labellisée Ligue contre le Cancer, Villejuif, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Portier
authors.affiliation: INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France.|Université Paris-Saclay, France.|Equipe Labellisée Ligue contre le Cancer, Villejuif, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Roders
authors.affiliation: INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France.|Université Paris-Saclay, France.|Equipe Labellisée Ligue contre le Cancer, Villejuif, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Arnoult
authors.affiliation: INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France.|Université Paris-Saclay, France.|Equipe Labellisée Ligue contre le Cancer, Villejuif, France.
authors.forename: Aimé
authors.initials: A
authors.lastname: Vazquez
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003600:Cytosol / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008213:Lymphocyte Activation; D008928:Mitochondria / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C000595707:BCL2 protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Burkitt’s lymphoma; PUMA; apoptosis; mitochondria; translocation