Many aspects of Wip1 signaling in the stress response consist of feedback loops. For example, DNA damage activates p53, which induces Wip1 expression. Once expressed, Wip1 negatively regulates p53 either by dephosphorylation and subsequent inactivation or by destabilization of the p53 protein through Mdm2. The same is true for NF-kappaB and upstream regulators of Wip1 such as ATM and p38. Depending on the nature of the stress and the cellular context, NF-kappaB, ATM or p38 each can upregulate Wip1, and Wip1 then dephosphorylates and inactivates NF-kappaB, ATM or p38. These negative feedback loops in Wip1 signaling highlight its physiological role in response to stress, i.e. it dampens the stress response to help return the cell to a homeostatic state.
