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- W97094622 abstract "IL-7 is required for T-cell development both in mouse and humans and for T-cell homeostasis in the periphery. Some of the downstream signal transducers from the IL-7 receptor are members of the Bcl-2 family of proteins associated with mitochondrial apoptosis. Mcl-1, one of the anti-apoptotic members of Bcl-2 family, became of particular interest when it was discovered that IL-7 upregulates Mcl-1 mRNA expression in T cells. This suggests that Mcl-1 may contribute to the survival functions of IL-7. In this study, we showed that the deficiency of T–cell development in IL-7Rα KO mice could be rescued by reconstitution of IL-7Rα deficient bone marrow by retrovirus expressing a mouse Mcl-1 construct. To further investigate the molecular mechanism of IL-7 regulation of Mcl-1, we used an IL-7-dependent murine thymic cell line D1. Deprivation of IL-7 from D1 cells or lymph node cells caused Mcl-1 protein degradation by 6 hrs. Overexpression of Mcl-1 protected D1 cells from the death induced by IL-7 deprivation. Compared to intact Mcl-1, the truncated form of Mcl-1 (Δ375), with deletion of 375 nucleotides from its 5′end, showed more potent anti-apoptotic activity, suggesting the 5′end of Mcl-1 might contain regulatory domains. In human Mcl-1 the lysine in the 5′ end of the gene was identified as the target site for ubiquitin. Based on this finding, we hypothesized that the lysine found in the mouse Mcl-1 would share this function. To test this hypothesis, we mutated the first three lysine residues (39, 80, and 117) to alanine at mouse Mcl-1 (Mcl 3KR) and tested its protein stability and its ability to prevent apoptosis. Mcl 3KR showed enhanced protein stability, and also provided D1 cells with more protection, compared to WT Mcl-1, after 3 to 4 days of IL-7 deprivation. Our findings suggest that Mcl-1 plays an important role protection of T-cell survival by IL-7. IL-7 strongly promotes Mcl-1 stability, possible by controlling lysine-directed ubiquitination." @default.
- W97094622 created "2016-06-24" @default.
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- W97094622 date "2008-03-01" @default.
- W97094622 modified "2023-09-25" @default.
- W97094622 title "Interleukin (IL)‐7 promotes T‐cell survival by stabilization of Mcl‐1" @default.
- W97094622 doi "https://doi.org/10.1096/fasebj.22.1_supplement.843.1" @default.
- W97094622 hasPublicationYear "2008" @default.
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