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miR-155 Controls Lymphoproliferation in LAT Mutant Mice by Restraining T-Cell Apoptosis via SHIP-1/mTOR and PAK1/FOXO3/BIM Pathways.
- Source :
-
PloS one [PLoS One] 2015 Jun 29; Vol. 10 (6), pp. e0131823. Date of Electronic Publication: 2015 Jun 29 (Print Publication: 2015). - Publication Year :
- 2015
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Abstract
- Linker for Activation of T cells (LAT) is an adapter protein that is essential for T cell function. Knock-in mice with a LAT mutation impairing calcium flux develop a fatal CD4+ lymphoproliferative disease. miR-155 is a microRNA that is correlated with hyperproliferation in a number of cancers including lymphomas and leukemias and is overexpressed in mutant LAT T cells. To test whether miR-155 was merely indicative of T cell activation or whether it contributes to lymphoproliferative disease in mutant LAT mice, we interbred LAT mutant and miR-155-deficient mice. miR-155 deficiency markedly inhibited lymphoproliferative disease by stimulating BIM-dependent CD4+ T cell apoptosis, even though ERK activation and T cell proliferation were increased in double mutant CD4+ T cells. Bim/Bcl2l11 expression is activated by the forkhead transcription factor FOXO3. Using miR-155-deficient, LAT mutant T cells as a discovery tool, we found two connected pathways that impact the nuclear translocation and activation of FOXO3 in T cells. One pathway is mediated by the inositide phosphatase SHIP-1 and the serine/threonine kinases AKT and PDK1. The other pathway involves PAK1 and JNK kinase activation. We define crosstalk between the two pathways via the kinase mTOR, which stabilizes PAK1. This study establishes a role for PAK1 in T cell apoptosis, which contrasts to its previously identified role in T cell proliferation. Furthermore, miR-155 regulates the delicate balance between PAK1-mediated proliferation and apoptosis in T cells impacting lymphoid organ size and function.
- Subjects :
- Adaptor Proteins, Signal Transducing metabolism
Animals
Apoptosis Regulatory Proteins metabolism
Bcl-2-Like Protein 11
Cell Proliferation
Forkhead Box Protein O3
Forkhead Transcription Factors metabolism
Humans
Inositol Polyphosphate 5-Phosphatases
Jurkat Cells
Lymphocyte Activation immunology
Lymphoproliferative Disorders genetics
Lymphoproliferative Disorders immunology
Lymphoproliferative Disorders pathology
Membrane Proteins metabolism
Mice, Inbred C57BL
Mice, Mutant Strains
MicroRNAs genetics
Mutation genetics
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
Phosphoproteins metabolism
Proto-Oncogene Proteins metabolism
T-Lymphocytes cytology
p21-Activated Kinases metabolism
Adaptor Proteins, Signal Transducing genetics
Apoptosis
Membrane Proteins genetics
MicroRNAs metabolism
Phosphoproteins genetics
Phosphoric Monoester Hydrolases metabolism
Signal Transduction
T-Lymphocytes immunology
TOR Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 10
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 26121028
- Full Text :
- https://doi.org/10.1371/journal.pone.0131823