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Systems analysis of phosphorylation-regulated Bcl-2 interactions establishes a model to reconcile the controversy over the significance of Bcl-2 phosphorylation.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2019 Feb; Vol. 176 (3), pp. 491-504. Date of Electronic Publication: 2018 Dec 26. - Publication Year :
- 2019
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Abstract
- Background and Purpose: The biological significance of the multi-site phosphorylation of Bcl-2 at its loop region (T69, S70 and S87) has remained controversial for decades. This is a major obstacle for understanding apoptosis and anti-tumour drug development.<br />Experimental Approach: We established a mathematical model into which a phosphorylation and de-phosphorylation process of Bcl-2 was integrated. Paclitaxel-treated breast cancer cells were used as experimental models. Changes in the kinetics of binding with its critical partners, induced by phosphorylation of Bcl-2 were experimentally obtained by surface plasmon resonance, using a phosphorylation-mimicking mutant EEE-Bcl-2 (T69E, S70E and S87E).<br />Key Results: Mathematical simulations combined with experimental validation showed that phosphorylation regulates Bcl-2 with different dynamics depending on the extent of Bcl-2 phosphorylation and the phosphorylated Bcl-2-induced changes in binding kinetics. In response to Bcl-2 homology 3 (BH3)-only protein Bmf stress, Bcl-2 phosphorylation switched from diminishing to enhancing the Bcl-2 anti-apoptotic ability with increased phosphorylation of Bcl-2, and the turning point was 50% Bcl-2 phosphorylation induced by 0.2 μM paclitaxel treatment. In contrast, Bcl-2 phosphorylation enhanced the anti-apoptotic ability of Bcl-2 towards other BH3-only proteins Bim, Bad and Puma, throughout the entire phosphorylation procedure.<br />Conclusions and Implications: The model could accurately predict the effects of anti-tumour drugs that involve the Bcl-2 family pathway, as shown with ABT-199 or etoposide.<br /> (© 2018 The British Pharmacological Society.)
- Subjects :
- Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Apoptosis drug effects
Bridged Bicyclo Compounds, Heterocyclic chemistry
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Cell Proliferation drug effects
Drug Screening Assays, Antitumor
Etoposide chemistry
Etoposide pharmacology
Humans
Kinetics
Ligands
Phosphorylation drug effects
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 chemistry
Sulfonamides chemistry
Sulfonamides pharmacology
Tumor Cells, Cultured
Models, Biological
Proto-Oncogene Proteins c-bcl-2 metabolism
Surface Plasmon Resonance
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 176
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 30500985
- Full Text :
- https://doi.org/10.1111/bph.14555