8. Wip1 Expression and the Resolution of p38 MAPK Activation
Wild-type p53-induced phosphatase 1 (Wip1) is a serine/threonine phosphatase, which plays an essential role in the resolution of the DNA damage response by downregulating p38-p53 signaling during the recovery phase [74]. Wip1 is overexpressed in many tumors [75,76] and under-expressed in neurons in association with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) [77].
Stressors that induce the p38/MAPK response result in sustained phosphorylation of p53, which not only arrests the cell cycle but can also induce apoptosis when repair processes are overwhelmed with too many DNA double strand breaks. By dephosphorylating several tumor suppressors, most notably p53, Wip1 inhibits apoptosis and promotes tumorigenesis, tumor progression, invasion and metastasis [75].
Tumor cells are often somewhat reckless in proliferating even in the presence of DNA damage, which accelerates their mutation rate, whereas mature neurons are non-proliferating cells even in the absence of stressors. Because the base level of Wip1 is low in neurons, they are more vulnerable to apoptosis following p38/MAPK signaling, because the phosphorylated state is maintained for an extended period of time.
Culmsee and Mattson have commented on the role of p53 in neuronal apoptosis: “p53 production is rapidly increased in neurons in response to a range of insults including DNA damage, oxidative stress, metabolic compromise, and cellular calcium overload” [78]. Their main thesis is that p53 upregulation leads to apoptosis in neurons that eventually results in symptoms of neurodegenerative disease, and they suggested that agents that inhibit p53 may be an effective therapy for neurodegenerative disease [78].
Wip1 expression is controlled through a complicated regulatory process, which begins with p38/MAPK activation. Perhaps surprisingly, Wip1 transcription is upregulated by phosphorylated p53, simultaneous with the upregulation of many tumor suppressor genes, but its translation into protein is delayed. This is because miR-16 is also induced by p53 [79], and this microRNA suppresses translation and promotes clearance of Wip1 RNA [76]. As the repair process progresses, the level of miR-16 falls, such that Wip1 becomes functional only after a delay period, during which the neuron either recovers from the damage or undergoes apoptosis. As more and more neurons die, the symptoms of impaired cognition and memory start to become manifest [78].