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Results: 1 to 7 of 7

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Protein phosphatase 2A family members (PP2A and PP6) associate with U1 snRNP and the spliceosome during pre-mRNA splicing.
Kamoun M, Filali M, Murray MV, Awasthi S, Wadzinski BE
(2013) Biochem Biophys Res Commun 440: 306-11
MeSH Terms: HEK293 Cells, HeLa Cells, Humans, Phosphoprotein Phosphatases, Phosphorylation, Protein Phosphatase 2, RNA Splicing, Ribonucleoprotein, U1 Small Nuclear, Ribonucleoprotein, U2 Small Nuclear, Spliceosomes, Thymocytes
Show Abstract · Added March 7, 2014
Protein phosphorylation and dephosphorylation are both important for multiple steps in the splicing pathway. Members of the PP1 and PP2A subfamilies of phospho-serine/threonine phosphatases play essential but redundant roles in the second step of the splicing reaction. PP6, a member of the PP2A subfamily, is the mammalian homolog of yeast Sit4p and ppe1, which are involved in cell cycle regulation; however, the involvement of PP6 in the splicing pathway remains unclear. Here we show that PP2A family members physically associate with the spliceosome throughout the splicing reaction. PP2A holoenzyme and PP6 were found stably associated with U1 snRNP. Together our findings indicate that these phosphatases regulate splicing catalysis involving U1 snRNP and suggest an important evolutionary conserved role of PP2A family phosphatases in pre-mRNA splicing.
Copyright © 2013 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
11 MeSH Terms
The transcriptional repressor NKAP is required for the development of iNKT cells.
Thapa P, Das J, McWilliams D, Shapiro M, Sundsbak R, Nelson-Holte M, Tangen S, Anderson J, Desiderio S, Hiebert S, Sant'angelo DB, Shapiro VS
(2013) Nat Commun 4: 1582
MeSH Terms: Animals, Cell Survival, Gene Deletion, Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor, Histone Deacetylases, Mice, Mice, Knockout, Natural Killer T-Cells, Organ Specificity, Receptors, Antigen, T-Cell, alpha-beta, Receptors, Notch, Recombination, Genetic, Repressor Proteins, Thymocytes
Show Abstract · Added March 26, 2014
Invariant natural killer T cells have a distinct developmental pathway from conventional αβ T cells. Here we demonstrate that the transcriptional repressor NKAP is required for invariant natural killer T cell but not conventional T cell development. In CD4-cre NKAP conditional knockout mice, invariant natural killer T cell development is blocked at the double-positive stage. This cell-intrinsic block is not due to decreased survival or failure to rearrange the invariant Vα14-Jα18 T cell receptor-α chain, but is rescued by overexpression of a rec-Vα14-Jα18 transgene at the double-positive stage, thus defining a role for NKAP in selection into the invariant natural killer T cell lineage. Importantly, deletion of the NKAP-associated protein histone deacetylase 3 causes a similar block in the invariant natural killer T cell development, indicating that NKAP and histone deacetylase 3 functionally interact to control invariant natural killer T cell development.
1 Communities
1 Members
0 Resources
14 MeSH Terms
The loss of the BH3-only Bcl-2 family member Bid delays T-cell leukemogenesis in Atm-/- mice.
Biswas S, Shi Q, Wernick A, Aiello A, Zinkel SS
(2013) Cell Death Differ 20: 869-77
MeSH Terms: Animals, Annexin A5, Apoptosis, Ataxia Telangiectasia Mutated Proteins, BH3 Interacting Domain Death Agonist Protein, Cell Cycle Proteins, Checkpoint Kinase 1, Chromosomal Proteins, Non-Histone, DNA Damage, DNA-Binding Proteins, Disease Models, Animal, Female, Leukemia, T-Cell, Male, Mice, Mice, Knockout, Protein Kinases, Protein-Serine-Threonine Kinases, T-Lymphocytes, Thymocytes, Tumor Suppressor Proteins, Tumor Suppressor p53-Binding Protein 1
Show Abstract · Added August 22, 2013
Multicellular organisms maintain genomic integrity and resist tumorigenesis through a tightly regulated DNA damage response (DDR) that prevents propagation of deleterious mutations either through DNA repair or programmed cell death. An impaired DDR leads to tumorigenesis that is accelerated when programmed cell death is prevented. Loss of the ATM (ataxia telangiectasia mutated)-mediated DDR in mice results in T-cell leukemia driven by accumulation of DNA damage accrued during normal T-cell development. Pro-apoptotic BH3-only Bid is a substrate of Atm, and Bid phosphorylation is required for proper cell cycle checkpoint control and regulation of hematopoietic function. In this report, we demonstrate that, surprisingly, loss of Bid increases the latency of leukemogenesis in Atm-/- mice. Bid-/-Atm-/- mice display impaired checkpoint control and increased cell death of DN3 thymocytes. Loss of Bid thus inhibits T-cell tumorigenesis by increasing clearance of damaged cells, and preventing propagation of deleterious mutations.
0 Communities
1 Members
0 Resources
22 MeSH Terms
Epigenetic regulation of the Ink4a-Arf (Cdkn2a) tumor suppressor locus in the initiation and progression of Notch1-driven T cell acute lymphoblastic leukemia.
Volanakis EJ, Boothby MR, Sherr CJ
(2013) Exp Hematol 41: 377-86
MeSH Terms: Animals, Binding Sites, Bone Marrow Cells, Cell Line, Cell Transformation, Neoplastic, Cells, Cultured, Coculture Techniques, Cyclin-Dependent Kinase Inhibitor p16, Disease Progression, Dogs, Epigenesis, Genetic, Flow Cytometry, Gene Expression, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mutation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Receptor, Notch1, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, T-Lymphocytes, Thymocytes, Tumor Suppressor Protein p14ARF
Show Abstract · Added December 10, 2013
Activating mutations of NOTCH1 and deletion of the INK4A-ARF (CDKN2A) tumor suppressor locus are two of the most frequent genetic alterations in T cell acute lymphoblastic leukemia (T-ALL). In a murine model of T-ALL induced by the intracellular domain of Notch1 (ICN1), the genetic interaction between ICN1 signaling and Arf inactivation is developmentally stage-specific, with a more pronounced requirement for Arf deletion in thymocytes than in bone marrow precursors targeted for transformation. In the thymus, the target cell for transformation is a CD4 and CD8 double-negative progenitor that undergoes T cell receptor beta-chain rearrangement, a cell type in which polycomb silencing of Ink4a-Arf is normally requisite. Epigenetic remodeling during tumor progression licenses Arf as a tumor suppressor and in turn provides the selective pressure for Ink4a-Arf deletion in clonal T-ALLs that emerge.
Copyright © 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
0 Communities
2 Members
0 Resources
25 MeSH Terms
Reciprocal regulation of Rag expression in thymocytes by the zinc-finger proteins, Zfp608 and Zfp609.
Reed NP, Henderson MA, Oltz EM, Aune TM
(2013) Genes Immun 14: 7-12
MeSH Terms: Animals, DNA-Binding Proteins, Gene Expression Regulation, Homeodomain Proteins, Mice, Mice, Inbred BALB C, Repressor Proteins, Thymocytes, Trans-Activators, Transcription, Genetic, Transcriptional Activation, Zinc Fingers
Show Abstract · Added December 10, 2013
Recombination-activating gene 1 (Rag1) and Rag2 enzymes are required for T cell receptor assembly and thymocyte development. The mechanisms underlying the transcriptional activation and repression of Rag1 and Rag2 are incompletely understood. The zinc-finger protein, Zfp608, represses Rag1 and Rag2 expression when expressed in thymocytes blocking T-cell maturation. Here we show that the related zinc-finger protein, Zfp609, is necessary for Rag1 and Rag2 expression in developing thymocytes. Zfp608 represses Rag1 and Rag2 expression indirectly by repressing the expression of Zfp609. Thus, the balance of Zfp608 and Zfp609 plays a critical role in regulating Rag1 and Rag2 expression, which may manifest itself not only during development of immature thymocytes into mature T cells but also in generation of the T-cell arm of the adaptive immune system, which does not fully develop until after birth.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia.
Lee K, Nam KT, Cho SH, Gudapati P, Hwang Y, Park DS, Potter R, Chen J, Volanakis E, Boothby M
(2012) J Exp Med 209: 713-28
MeSH Terms: Active Transport, Cell Nucleus, Animals, Carrier Proteins, Cell Differentiation, Cell Lineage, Forkhead Box Protein O1, Forkhead Transcription Factors, Mice, Mice, Inbred C57BL, NF-kappa B, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Rapamycin-Insensitive Companion of mTOR Protein, Receptors, Notch, TOR Serine-Threonine Kinases, Thymocytes
Show Abstract · Added December 10, 2013
Notch plays critical roles in both cell fate decisions and tumorigenesis. Notch receptor engagement initiates signaling cascades that include a phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway. Mammalian TOR (mTOR) participates in two distinct biochemical complexes, mTORC1 and mTORC2, and the relationship between mTORC2 and physiological outcomes dependent on Notch signaling is unknown. In this study, we report contributions of mTORC2 to thymic T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch. Conditional deletion of Rictor, an essential component of mTORC2, impaired Notch-driven proliferation and differentiation of pre-T cells. Furthermore, NF-κB activity depended on the integrity of mTORC2 in thymocytes. Active Akt restored NF-κB activation, a normal rate of proliferation, and differentiation of Rictor-deficient pre-T cells. Strikingly, mTORC2 depletion lowered CCR7 expression in thymocytes and leukemic cells, accompanied by decreased tissue invasion and delayed mortality in T-ALL driven by Notch. Collectively, these findings reveal roles for mTORC2 in promoting thymic T cell development and T-ALL and indicate that mTORC2 is crucial for Notch signaling to regulate Akt and NF-κB.
2 Communities
3 Members
0 Resources
18 MeSH Terms
GSK3-mediated instability of tubulin polymers is responsible for the failure of immature CD4+CD8+ thymocytes to polarize their MTOC in response to TCR stimulation.
Cunningham NR, Hinchcliff EM, Kutyavin VI, Beck T, Reid WA, Punt JA
(2011) Int Immunol 23: 693-700
MeSH Terms: Aminophenols, Animals, Blotting, Western, CD4 Antigens, CD8 Antigens, Cell Differentiation, Enzyme Inhibitors, Female, Flow Cytometry, Gene Expression Regulation, Developmental, Glycogen Synthase Kinase 3, Lymphocyte Activation, Maleimides, Mice, Mice, Inbred C57BL, Microtubule-Organizing Center, Microtubules, Polymerization, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Thymocytes, Tubulin
Show Abstract · Added January 11, 2016
Although mature T cells divide and differentiate when they receive strong TCR stimulation, most immature CD4+CD8+ thymocytes die. The molecular basis for this marked difference in response is not known. Observations that TCR-stimulated CD4+CD8+ thymocytes fail to polarize their microtubule-organizing center (MTOC), one of the first events that occurs upon antigen activation of mature T cells, suggests that TCR signaling routes in immature and mature T cells diverge early and upstream of MTOC polarization. To better understand the source of the divergence, we examined the molecular basis for the difference in TCR-mediated MTOC polarization. We show that unstable microtubules are a feature of immature murine CD4+CD8+ thymocytes, which also exhibit higher levels of glycogen synthase kinase 3 (GSK3) activity, a known inhibitor of microtubule stability. Importantly, CD4+CD8+ thymocytes gained the ability to polarize their MTOC in response to TCR signals when GSK3 activity was inhibited. GSK3 inhibition also abrogated TCR-mediated apoptosis of immature thymocytes. Together, our results suggest that a developmentally regulated difference in GSK3 activity has a major influence on immature CD4+CD8+ thymocyte versus mature T-cell responses to TCR stimulation.
0 Communities
1 Members
0 Resources
23 MeSH Terms