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Assays for the Degradation of Misfolded Proteins in Cells
Published on: August 28, 2016
Systematic Protein Level Regulation via Degradation Machinery Induced by Genotoxic Drugs
Kohei Kume1,2, Kazushige Ishida, Miyuki Ikeda
1Medical Innovation for Advanced Science and Technology program (MIAST), Iwate Medical University , Morioka, Iwate 020-8505, Japan.
Abstract:
In this study we monitored protein dynamics in response to cisplatin, 5-fluorouracil, and irinotecan with different concentrations and administration modes using "reverse-phase" protein arrays (RPPAs) in order to gain comprehensive insight into the protein dynamics induced by genotoxic drugs. Among 666 protein time-courses, 38% exhibited an increasing trend, 32% exhibited a steady decrease, and 30% fluctuated within 24 h after drug exposure. We analyzed almost 12,000 time-course pairs of protein levels based on the geometrical similarity by correlation distance (dCor). Twenty-two percent of the pairs showed dCor > 0.8, which indicates that each protein of the pair had similar dynamics. These trends were disrupted by a proteasome inhibitor, MG132, suggesting that the protein degradation system was activated in response to the drugs. Among the pairs with high dCor, the average dCor of pairs with apoptosis-related protein was significantly higher than those without, indicating that regulation of protein levels was induced by the drugs. These results suggest that the levels of numerous functionally distinct proteins may be regulated by common degradation machinery induced by genotoxic drugs.
Insights
Genotoxic drugs like cisplatin alter protein levels, with many proteins showing similar dynamic changes. This suggests a common protein degradation system is activated by these cancer-fighting agents.
Area of Science:
- Proteomics
- Molecular Biology
- Cancer Drug Research
Background:
- Genotoxic drugs are crucial in cancer therapy.
- Understanding their impact on cellular proteomes is vital.
- Protein dynamics following drug exposure remain incompletely understood.
Purpose of the Study:
- To comprehensively map protein dynamics induced by genotoxic drugs.
- To investigate the coordinated regulation of protein levels.
- To identify the role of protein degradation in drug response.
Main Methods:
- Utilized reverse-phase protein arrays (RPPAs) to monitor protein dynamics.
- Analyzed 666 protein time-courses across various drug concentrations and modes.
- Employed correlation distance (dCor) to assess similarity in protein level dynamics.
Main Results:
- 38% of proteins showed increasing trends, 32% decreasing, and 30% fluctuating within 24h.
- 22% of protein pairs exhibited highly correlated dynamics (dCor > 0.8).
- Proteasome inhibition (MG132) disrupted these trends, indicating activation of protein degradation.
Conclusions:
- Genotoxic drugs induce widespread protein dynamics, with many proteins regulated coordinately.
- Apoptosis-related proteins showed significantly higher correlation in their dynamics.
- Common protein degradation machinery is likely involved in regulating protein levels in response to genotoxic stress.
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