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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., Hossini, A.M., Gillissen, B., Daniel, P.T., 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 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Volume: | 7 |
| Number: | 4 |
| 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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