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. Regulation of FOXO1 protein activation. A) Regulatory network revealed in paleo-ESF of the opossum Monodelphis domestica (for evidence, see Erkenbrack, et al., 2018). Progesterone leads to the inhibition of degradation of FOXO1 protein, which leads to its accumulation in the cytoplasm. Presence of ROS and cAMP, as well as PGE2 through the activation of PGE2 receptor 4 (PTGER4 aka EP4) stimulation, inhibits the nuclear export of FOXO1 and thus retention of FOXO1 in the nucleus, where it positively influences the transcription of antioxidant enzymes like catalase and gluthathione peroxidase. In this model we assume that PGE2 acts through PKA and cAMP to induce the NADPH oxidase 4 (NOX4) to produce the cytoplasmic ROS, which is parsimonious but not yet directly shown. B) Ancestral activation of FOXO1 in response to ROS, through activation of ERK1/2 signaling found in many other cells. The network in the opossum ESF, as shown in A), is likely derived from this generic oxidative stress pathway by two evolutionary events. First, the evolution of NOX4 activation by PGE2, though this also could be a generic pathway since PGE2 has been shown to activate NOX4 through PTGER4 in liver cells 46 . Second, the inhibition of FOXO1 degradation by progesterone through its receptor isoform A, PGR-A. In this way, the activation of FOXO1 through the generic oxidative stress reaction becomes internalized, i.e., activated through physiological signals rather than stressors.