Cycles of self-limiting ATF4 regulation: a potential dynamical motif.

The ATF4 transcription factor network plays a critical role in controlling the shift from pro-survival to pro-apoptosis regimes when mammalian cells experience starvation, viral infection, ER or oxidative stresses. Continued activation of pro-survival pathways with failure to initiate apoptosis under chronic stress is associated with dysfunction of the ATF4 network and is a feature of cells undergoing tumorigenesis. The shift between the pro-survival and pro-apoptosis regimes is observed to be switch-like over time but the mechanisms by which this shift occurs, or which components contribute to this emergent behaviour, are not fully understood. It may be possible to gain a better understanding of the factors that control this network by studying it in contextually isolated modules identifying unique dynamical motifs that may contribute to the ATF4 network's emergent dynamical behaviour. Self-limiting ATF4 regulation has been observed with respect to CARE (C/EBP-ATF Response Element)-containing targets under amino acid limitation and describes behaviour in which the expression of these targets is initially promoted and then later repressed by other targets in a timed program. A model of ATF4's regulation of Cat-1, an amino-acid transporter that is upregulated in response to amino-acid starvation, is evaluated as a potential example of a self-limiting motif.