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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.

Authors :
Song T
Wang P
Yu X
Wang A
Chai G
Fan Y
Zhang Z
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

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.)

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