期刊
CELL SYSTEMS
卷 2, 期 2, 页码 112-121出版社
CELL PRESS
DOI: 10.1016/j.cels.2016.01.012
关键词
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资金
- NIH [1-R21-AI105970, 1-DP2-OD006464]
- American Cancer Society [120668-RSG-11047-01-DMC]
- Pew Charitable Trusts [2008-000410-006]
- David and Lucile Packard Foundation [2009-34710]
Chemical inhibition and genetic knockdown of enzymes are not equivalent in cells, but network-level mechanisms that cause discrepancies between knockdown and inhibitor perturbations are not understood. Here we report that enzymes regulated by negative feedback are robust to knockdown but susceptible to inhibition. Using the Raf-MEK-ERK kinase cascade as a model system, we find that ERK activation is resistant to genetic knockdown of MEK but susceptible to a comparable degree of chemical MEK inhibition. We demonstrate that negative feedback from ERK to Raf causes this knock-down-versus-inhibitor discrepancy in vivo. Exhaustive mathematical modeling of three-tiered enzyme cascades suggests that this result is general: negative autoregulation or feedback favors inhibitor potency, whereas positive autoregulation or feedback favors knockdown potency. Our findings provide a rationale for selecting pharmacologic versus genetic perturbations in vivo and point out the dangers of using knockdown approaches in search of drug targets.
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