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.
Highlights
Apoptosis is regulated by two major groups of proteins: caspases and the proteins of the Bcl-2 family
We previously observed that PUMA expression was strongly upregulated in response to mitogenic activation in vitro, in normal human B lymphocytes (Figure 1A)
We previously observed that the amounts of Bcl-2, BclXL and Mcl-1 were stable after mitogenic activation, indicating that the increase in PUMA expression was not counterbalanced by the production of large amounts of the anti-apoptotic counterparts of PUMA
Summary
Apoptosis is regulated by two major groups of proteins: caspases and the proteins of the Bcl-2 family. The third group, BH3-only proteins, contains proteins regulating the other two groups and controlling the pro/antiapoptotic balance This group can be classified into two subgroups: (i) BH3-only proteins binding only one subgroup of anti-apoptotic molecules (e.g. Bad and Bik interact with and inhibit the Bcl-2 subgroup whereas Noxa and Bmf interact with the Mcl-1 subgroup) and (ii) BH3-only proteins able to interact with all anti-apoptotic molecules, such as tBid, Bim and PUMA. These two subgroups differ in their capacity to activate pro-apoptotic proteins directly. The proteins of the second subgroup (tBid, Bim and PUMA) have been reported to interact with and activate Bax and Bak directly [1,2,3]
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