In non-transformed cells Bak activates upon loss of anti-apoptotic Bcl-XL and Mcl-1 but in the absence of active BH3-only proteins.

Abstract

Mitochondrial apoptosis is controlled by proteins of the B-cell lymphoma 2 (Bcl-2) family. Pro-apoptotic members of this family, known as BH3-only proteins, initiate activation of the effectors Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), which is counteracted by anti-apoptotic family members. How the interactions of Bcl-2 proteins regulate cell death is still not entirely clear. Here, we show that in the absence of extrinsic apoptotic stimuli Bak activates without detectable contribution from BH3-only proteins, and cell survival depends on anti-apoptotic Bcl-2 molecules. All anti-apoptotic Bcl-2 proteins were targeted via RNA interference alone or in combinations of two in primary human fibroblasts. Simultaneous targeting of B-cell lymphoma-extra large and myeloid cell leukemia sequence 1 led to apoptosis in several cell types. Apoptosis depended on Bak whereas Bax was dispensable. Activator BH3-only proteins were not required for apoptosis induction as apoptosis was unaltered in the absence of all BH3-only proteins known to activate Bax or Bak directly, Bcl-2-interacting mediator of cell death, BH3-interacting domain death agonist and p53-upregulated modulator of apoptosis. These findings argue for auto-activation of Bak in the absence of anti-apoptotic Bcl-2 proteins and provide evidence of profound differences in the activation of Bax and Bak.

• Authors: D Senft, A Weber, F Saathoff, C Berking, M V Heppt, C Kammerbauer, S Rothenfusser, S Kellner, Z Kurgyis, R Besch, G Häcker
• Journal: Cell death & disease (Cell Death Dis) Vol. 6 Pg. e1996 (Nov 26 2015) ISSN: 2041-4889 [Electronic] England
• PMID: 26610208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BAK1 protein, human
• BCL2L1 protein, human
• MCL1 protein, human
• Mitochondrial Membrane Transport Proteins
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• RTL10 protein, human
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-X Protein

Topics

• Animals
• Apoptosis (physiology)
• Cell Survival (physiology)
• Cells, Cultured
• Endothelial Cells (ultrastructure)
• Fibroblasts
• Humans
• Keratinocytes
• Mice
• Mitochondria (metabolism)
• Mitochondrial Membrane Transport Proteins
• Myeloid Cell Leukemia Sequence 1 Protein (deficiency, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (deficiency, metabolism)
• Transfection
• bcl-2 Homologous Antagonist-Killer Protein (metabolism)
• bcl-X Protein (deficiency, metabolism)