Human Stress Response Specificity through Biochemical Resonance Selectivity

In eukaryotes, the mitogen activated protein kinase (MAPK) cascade, a multilayered interconnected network of enzymes, connects external stimuli to gene regulation, determining cellular fate ¹ . Environmental stress sensed by a cell starts a complex chain of reactions between MAPK enzymes that ultimately activates the master stress response regulator protein p38 MAPK ^2,3 . Thus activated, p38 must then selectively activate targets from a pool of hundreds to initiate appropriate cellular responses ³ . Mechanisms for how p38 performs this selection remain unclear ^4,5 . Here we show that human p38 target selectivity is based on the same principles as modern electronic telecommunications systems, except using waves of chemicals rather than electromagnetic fields or electric currents. p38 encodes information about stimuli as different frequency oscillations of its activation state, and targets are selected through frequency-dependent resonance of oscillating biochemical reactions between p38 and its targets. We demonstrate this mechanism by activating various genetic responses in human cells by applying only sugar at different frequencies. These results unify observations of oscillating signaling components and altered responses ^6–19 into a coherent framework to understand and control human gene expression. As failures of this mechanism may contribute to some p38-associated diseases ^2,20–28 , these findings may have implications for pharmaceutical development and therapeutic strategies.