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Mutual regulation of Bcl-2 proteins independent of the BH3 domain as shown by the BH3-lacking protein Bcl-x(AK)

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Item Type:Article
Title:Mutual regulation of Bcl-2 proteins independent of the BH3 domain as shown by the BH3-lacking protein Bcl-x(AK)
Creators Name:Ploetz, M. and Hossini, A.M. and Gillissen, B. and Daniel, P.T. and Stockfleth, E. and Eberle, J.
Abstract:The BH3 domain of Bcl-2 proteins was regarded as indispensable for apoptosis induction and for mutual regulation of family members. We recently described Bcl-x(AK), a proapoptotic splice product of the bcl-x gene, which lacks BH3 but encloses BH2, BH4 and a transmembrane domain. It remained however unclear, how Bcl-x(AK) may trigger apoptosis.For efficient overexpression, Bcl-x(AK) was subcloned in an adenoviral vector under Tet-OFF control. The construct resulted in significant apoptosis induction in melanoma and nonmelanoma cell lines with up to 50% apoptotic cells as well as decreased cell proliferation and survival. Disruption of mitochondrial membrane potential, and cytochrome c release clearly indicated activation of the mitochondrial apoptosis pathways. Both Bax and Bak were activated as shown by clustering and conformation analysis. Mitochondrial translocation of Bcl-x(AK) appeared as an essential and initial step. Bcl-x(AK) was critically dependent on either Bax or Bak, and apoptosis was abrogated in Bax/Bak double knockout conditions as well by overexpression of Bcl-2 or Bcl-x(L). A direct interaction with Bcl-2, Bax, Bad, Noxa or Puma was however not seen by immunoprecipitation. Thus besides BH3-mediated interactions, there exists an additional way for mutual regulation of Bcl-2 proteins, which is independent of the BH3. This pathway appears to play a supplementary role also for other proapoptotic family members, and its unraveling may help to overcome therapy resistance in cancer.
Keywords:Apoptosis, bcl-X Protein, bcl-2 Homologous Antagonist-Killer Protein, Caspases, Cytochromes c, Membrane Proteins, Mitochondria, Mitochondrial Membrane Potential, Peptide Fragments, Protein Interaction Domains and Motifs, Protein Transport, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Tertiary Protein Structure, Tumor Cell Line
Source:PLoS ONE
Publisher:Public Library of Science (U.S.A.)
Page Range:e34549
Date:10 April 2012
Official Publication:https://doi.org/10.1371/journal.pone.0034549
PubMed:View item in PubMed

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