Related Experiment Video
Updated: Jul 16, 2025
Simultaneous Assessment of Kinship, Division Number, and Phenotype via Flow Cytometry for Hematopoietic Stem and Progenitor Cells
Published on: March 24, 2023
Hsp70-Bim incoherent feedforward loop contributes to cell-fate heterogeneity and fractional killing
Fangkui Yin1, Ting Song1, Ziqian Wang1
1State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.
Background And Purpose:
Although chemotherapeutics or molecular targeted drugs often elicit profound initial responses, fractional killing capable of driving acquired resistance can persist. Identifying stress-induced negative feedback or an incoherent feedforward loop (IFFL), which may contribute to fractional killing, is urgently needed.
Experimental Approach:
Mathematical modelling was used to identify how and to what extent a recently reported Hsp70-Bim protein-protein interaction (PPI) contributes to the adaptation of the Bcl-2 network. Experimental validation was made by using a specific inhibitor of Hsp70-Bim PPI, S1g-2, as chemical tool. Bifurcation analysis and stochastic simulation were used for the theoretical study of the impact of Hsp70-Bim PPI on cell-fate heterogeneity and factional killing.
Key Results:
The Hsp70-Bim-AKT circuit forms an IFFL that greatly contributes to the adaptation of the Bcl-2-regulated apoptosis network, thus leading to fractional killing. This adaptive programme enhances noise-induced cell-fate heterogeneity by shifting from a saddle-node to a saddle-collision transition scenario.
Conclusion And Implications:
Hsp70-Bim IFFL serves as a molecular pathway induced by DNA damaging drugs or tyrosine kinase inhibitors that enabled fractional killing, whereby acquired resistance emerges. A synergistic strategy is unveiled for overcoming fractional killing by suppressing Hsp70-Bim PPI.
Insights
A newly identified incoherent feedforward loop (IFFL) involving Hsp70-Bim promotes fractional killing and drug resistance. Suppressing this Hsp70-Bim interaction offers a synergistic strategy to overcome resistance in cancer therapy.
Area of Science:
- Cellular and Molecular Biology
- Systems Biology
- Cancer Therapeutics
Background:
- Chemotherapeutics and targeted drugs can lead to fractional killing, promoting acquired resistance.
- Identifying mechanisms like stress-induced feedback or incoherent feedforward loops (IFFLs) is crucial for understanding and overcoming resistance.
Purpose of the Study:
- To investigate the role of the Hsp70-Bim protein-protein interaction (PPI) in the adaptation of the Bcl-2 network and its contribution to fractional killing.
- To explore the Hsp70-Bim-AKT circuit as a potential IFFL driving resistance.
- To identify therapeutic strategies targeting the Hsp70-Bim PPI.
Main Methods:
- Mathematical modeling to analyze the Hsp70-Bim PPI's impact on the Bcl-2 network.
- Experimental validation using the Hsp70-Bim PPI inhibitor S1g-2.
- Bifurcation analysis and stochastic simulations to study cell-fate heterogeneity and fractional killing.
Main Results:
- The Hsp70-Bim-AKT circuit forms an IFFL that drives adaptation in the Bcl-2 network, leading to fractional killing.
- This adaptive mechanism enhances cell-fate heterogeneity by altering the transition dynamics.
- The Hsp70-Bim IFFL is induced by DNA damaging drugs and tyrosine kinase inhibitors, facilitating acquired resistance.
Conclusions:
- The Hsp70-Bim IFFL is a key molecular pathway enabling fractional killing and the emergence of acquired resistance.
- Suppressing Hsp70-Bim PPI presents a synergistic strategy to overcome fractional killing and enhance cancer treatment efficacy.
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:37Restarting Stalled Replication Forks
02:36Cells Coordinate Growth and Proliferation
01:01Regulation of Hematopoietic Stem Cells
01:28The Cell Cycle Control System
Cyclins and cyclin-dependent kinases (Cdks) are the primary cell cycle regulators and...