Network Architecture Predisposes an Enzyme to Either Pharmacologic or Genetic Targeting.
Network Architecture Predisposes an Enzyme to Either Pharmacologic or Genetic Targeting.
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DOI：
10.1016/j.cels.2016.01.012
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发表时间：
2016-02-24
期刊：
影响因子：
9.3
通讯作者：
Janes KA
中科院分区：
文献类型：
--
作者：
Jensen KJ;Moyer CB;Janes KA
化学抑制和基因敲低酶是不等同的细胞，但网络水平的机制，导致敲低和抑制剂扰动之间的差异还不清楚。在这里，我们报告说，负反馈调节的酶是强大的击倒，但容易受到抑制。使用Raf-MEK-ERK激酶级联作为模型系统，我们发现ERK激活对MEK的遗传敲低具有抗性，但对相当程度的化学MEK抑制敏感。我们证明了ERK到Raf的负反馈导致了体内这种敲除与抑制剂的差异。三层酶级联的详尽数学建模表明，这一结果是普遍的：负自动调节或反馈有利于抑制剂的效力，而正自动调节或反馈有利于击倒效力。我们的研究结果为选择体内药理学与遗传学干扰提供了理论依据，并指出了使用敲除方法寻找药物靶点的危险。
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 knockdown-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.