Understanding non-linear effects from Hill-type dynamics with application to decoding of p53 signaling.

Analytical equations are derived depicting four possible scenarios resulting from pulsed signaling of a system subject to Hill-type dynamics. Pulsed Hill-type dynamics involves the binding of multiple signal molecules to a receptor and occurs e.g., when transcription factor p53 orchestrates cancer prevention, during calcium signaling, and during circadian rhythms. The scenarios involve: (i) enhancement of high-affinity binders compared to low-affinity ones, (ii) slowing reactions involving high-affinity binders, (iii) transfer of the clocking of low-affinity binders from the signal molecule to the products, and (iv) a unique clocking process that produces incremental increases in the activity of high-affinity binders with each signal pulse. In principle, these mostly non-linear effects could control cellular outcomes. An applications to p53 signaling is developed, with binding to most gene promoters identified as category (iii) responses. However, currently unexplained enhancement of high-affinity promoters such as CDKN1a (p21) by pulsed signaling could be an example of (i). In general, provision for all possible scenarios is required in the design of mathematical models incorporating pulsed Hill-type signaling as some aspect.