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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, RESULTS. Meshes: Animals, Apoptosis, Catalase, Cell Proliferation, Cell Survival, Forkhead Box Protein O1, Forkhead Transcription Factors, Hepatocyte Growth Factor, Humans, Mice, Mice, Transgenic, Models, Biological, Oxidative Stress, Proto-Oncogene Proteins, Reactive Oxygen Species, Signal Transduction, Superoxide Dismutase, T-Lymphocytes.
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Does mst1-FoxO signaling protect Naïve T lymphocytes from cellular oxidative stress in mice? Context: The Ste-20 family kinase Hippo restricts cell proliferation and promotes apoptosis for proper organ development in Drosophila. In C. elegans, Hippo homolog also regulates longevity. The mammalian Ste20-like protein kinase, Mst1, plays a role in apoptosis induced by various types of apoptotic stress. Mst1 also regulates peripheral naïve T cell trafficking and proliferation in mice. However, its functions in mammals are not fully understood. Here, we report that the Mst1-FoxO signaling pathway plays a crucial role in survival, but not apoptosis, of naïve T cells. In Mst1(-/-) mice, peripheral T cells showed impaired FoxO1/3 activation and decreased FoxO protein levels. Consistently, the FoxO targets, Sod2 and catalase, were significantly down-regulated in Mst1(-/-) T cells, thereby resulting in elevated levels of intracellular reactive oxygen species (ROS) and induction of apoptosis. Expression of constitutively active FoxO3a restored Mst1(-/-) T cell survival. Crossing Mst1 transgenic mice (Mst1 Tg) with Mst1(-/-) mice reduced ROS levels and restored normal numbers of peripheral naïve T cells in Mst1 Tg;Mst1(-/-) progeny. Interestingly, peripheral T cells from Mst1(-/-) mice were hypersensitive to gamma-irradiation and paraquat-induced oxidative stresses, whereas those from Mst1 Tg mice were resistant.
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These data support the hypothesis that tolerance to increased levels of intracellular ROS provided by the Mst1-FoxOs signaling pathway is crucial for the maintenance of naïve T cell homeostasis in the periphery. Final Decision: yes