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Subcellular localization of PUMA regulates its pro-apoptotic activity in Burkitt's lymphoma B cells.
Oncotarget 2015; 6(35):38181-94O

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+Show Affiliations

INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France. Université Paris-Saclay, France. Equipe Labellisée Ligue contre le Cancer, Villejuif, France.INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France. Université Paris-Saclay, France. Equipe Labellisée Ligue contre le Cancer, Villejuif, France.INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France. Université Paris-Saclay, France. Equipe Labellisée Ligue contre le Cancer, Villejuif, France.INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France. Université Paris-Saclay, France. Equipe Labellisée Ligue contre le Cancer, Villejuif, France.INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France. Université Paris-Saclay, France. Equipe Labellisée Ligue contre le Cancer, Villejuif, France.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26431330

Citation

Ambroise, Gorbatchev, et al. "Subcellular Localization of PUMA Regulates Its Pro-apoptotic Activity in Burkitt's Lymphoma B Cells." Oncotarget, vol. 6, no. 35, 2015, pp. 38181-94.
Ambroise G, Portier A, Roders N, et al. Subcellular localization of PUMA regulates its pro-apoptotic activity in Burkitt's lymphoma B cells. Oncotarget. 2015;6(35):38181-94.
Ambroise, G., Portier, A., Roders, N., Arnoult, D., & Vazquez, A. (2015). Subcellular localization of PUMA regulates its pro-apoptotic activity in Burkitt's lymphoma B cells. Oncotarget, 6(35), pp. 38181-94. doi:10.18632/oncotarget.5901.
Ambroise G, et al. Subcellular Localization of PUMA Regulates Its Pro-apoptotic Activity in Burkitt's Lymphoma B Cells. Oncotarget. 2015 Nov 10;6(35):38181-94. PubMed PMID: 26431330.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Subcellular localization of PUMA regulates its pro-apoptotic activity in Burkitt's lymphoma B cells. AU - Ambroise,Gorbatchev, AU - Portier,Alain, AU - Roders,Nathalie, AU - Arnoult,Damien, AU - Vazquez,Aimé, PY - 2015/04/30/received PY - 2015/09/17/accepted PY - 2015/10/3/entrez PY - 2015/10/3/pubmed PY - 2016/9/7/medline KW - Burkitt’s lymphoma KW - PUMA KW - apoptosis KW - mitochondria KW - translocation SP - 38181 EP - 94 JF - Oncotarget JO - Oncotarget VL - 6 IS - 35 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/26431330/Subcellular_localization_of_PUMA_regulates_its_pro_apoptotic_activity_in_Burkitt's_lymphoma_B_cells_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=5901 DB - PRIME DP - Unbound Medicine ER -