Oncotarget

Research Papers:

Subcellular localization of PUMA regulates its pro-apoptotic activity in Burkitt’s lymphoma B cells

Gorbatchev Ambroise, Alain Portier, Nathalie Roders, Damien Arnoult and Aimé Vazquez _

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Oncotarget. 2015; 6:38181-38194. https://doi.org/10.18632/oncotarget.5901

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Abstract

Gorbatchev Ambroise1,2,3, Alain Portier1,2,3, Nathalie Roders1,2,3, Damien Arnoult1,2,3 and Aimé Vazquez1,2,3

1 INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France

2 Université Paris-Saclay, France

3 Equipe Labellisée Ligue contre le Cancer, Villejuif, France

Correspondence to:

Aimé Vazquez, email:

Keywords: PUMA, Burkitt’s Lymphoma, apoptosis, translocation, mitochondria

Received: April 30, 2015 Accepted: September 17, 2015 Published: September 29, 2015

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.


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