The usage of alternative splice sites in mus musculus synaptotagmin-like 2 gene is modulated by cyclosporin A and FK506 in T-lymphocytes

Mascarell, Laurent; Auger, Rodolphe; Kanellopoulos, Jean; Truffa‐Bachi, Paolo

doi:10.1016/j.molimm.2005.10.019

Cited by 4 publications

(5 citation statements)

References 45 publications

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“…The top 20 up- and down-regulated genes are shown in Table 1. The highest inductions were for GLIPR1 (~30-fold), a gene hormonally-regulated in breast cancer cells [34], and SYTL2 (~12-fold), a trafficking protein also known as Breast Cancer-Associated antigen SGA-72M [35]. Several top up-regulated genes were associated with motility, adhesion, invasiveness, and metastasis in breast cancer or other cancers, such as GBP1 , ITGB6 , ITGA2 , and matrix metalloproteases MMP10 and MMP1 .…”

Section: Resultsmentioning

confidence: 99%

Characterization of a P-Rex1 gene signature in breast cancer cells

et al. 2016

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The Rac nucleotide Exchange Factor (Rac-GEF) P-Rex1 is highly expressed in breast cancer, specifically in the luminal subtype, and is an essential mediator of actin cytoskeleton reorganization and cell migratory responses induced by stimulation of ErbB and other tyrosine-kinase receptors. Heregulin (HRG), a growth factor highly expressed in mammary tumors, causes the activation of P-Rex1 and Rac1 in breast cancer cells via ErbB3, leading to a motile response. Since there is limited information about P-Rex1 downstream effectors, we carried out a microarray analysis to identify genes regulated by this Rac-GEF after stimulation of ErbB3 with HRG. In T-47D breast cancer cells, HRG treatment caused major changes in gene expression, including genes associated with motility, adhesion, invasiveness and metastasis. Silencing P-Rex1 expression from T-47D cells using RNAi altered the induction and repression of a subset of HRG-regulated genes, among them genes associated with extracellular matrix organization, migration, and chemotaxis. HRG induction of MMP10 (matrix metalloproteinase 10) was found to be highly sensitive both to P-Rex1 depletion and inhibition of Rac1 function by the GTPase Activating Protein (GAP) β2-chimaerin, suggesting the dependence of the P-Rex1/Rac1 pathway for the induction of genes critical for breast cancer invasiveness. Notably, there is a significant association in the expression of P-Rex1 and MMP10 in human luminal breast cancer, and their co-expression is indicative of poor prognosis.

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Section: Resultsmentioning

confidence: 99%

Characterization of a P-Rex1 gene signature in breast cancer cells

et al. 2016

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“…NFATs were found to cooperate with HDACs, where NFAT1c mediated HDAC-dependent transcriptional repression [57]. Moreover, both NFATs and HDACs were found to be involved in regulation of alternative splicing [41], [42], [49]. To check whether NFAT cooperates with HDACs in PC12 cells with different PMCA status we first analyzed the presence of various HDACs in total cellular lysates obtained from these cells.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, both NFATs and HDACs have been found to be involved in the regulation of alternative splicing. NFAT1 has been suggested to participate in the regulation of alternative splicing of the allograft inflammatory factor-1 gene [41], and of synaptotagmin-like 2 gene during activation of murine T-cells [42]. HDACs have been proposed to contribute to the process of alternative splicing by regulating co-transcriptional spliceosome assembly [51].…”

Section: Discussionmentioning

confidence: 99%

“…One of the transcription factors whose activity has been linked with alternative splicing is nuclear factor of activated T cells (NFAT). NFAT was found to influence the alternative splicing of mRNAs of allograft inflammatory factor-1 (AIF-1) [41], of interferon responsive transcript-1 (IRT-1) [20], and of synaptotagmin-like 2 protein [42]. Interestingly, NFAT has been proposed to be responsible for the control of the expression of the PMCA1 and PMCA4 isoforms [43]–[48].…”

Section: Introductionmentioning

confidence: 99%

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NFAT1 and NFAT3 Cooperate with HDAC4 during Regulation of Alternative Splicing of PMCA Isoforms in PC12 Cells

Kosiorek

Podszywałow-Bartnicka

Żylińska

et al. 2014

PLoS ONE

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BackgroundThe bulk of human genes undergo alternative splicing (AS) upon response to physiological stimuli. AS is a great source of protein diversity and biological processes and is associated with the development of many diseases. Pheochromocytoma is a neuroendocrine tumor, characterized by an excessive Ca2+-dependent secretion of catecholamines. This underlines the importance of balanced control of calcium transport via regulation of gene expression pattern, including different calcium transport systems, such as plasma membrane Ca2+-ATPases (PMCAs), abundantly expressed in pheochromocytoma chromaffin cells (PC12 cells). PMCAs are encoded by four genes (Atp2b1, Atp2b2, Atp2b3, Atp2b4), whose transcript products undergo alternative splicing giving almost 30 variants.ResultsIn this scientific report, we propose a novel mechanism of regulation of PMCA alternative splicing in PC12 cells through cooperation of the nuclear factor of activated T-cells (NFAT) and histone deacetylases (HDACs). Luciferase assays showed increased activity of NFAT in PC12 cells, which was associated with altered expression of PMCA. RT-PCR experiments suggested that inhibition of the transcriptional activity of NFAT might result in the rearrangement of PMCA splicing variants in PC12 cells. NFAT inhibition led to dominant expression of 2x/c, 3x/a and 4x/a PMCA variants, while in untreated cells the 2w,z/b, 3z,x/b,c,e,f, and 4x/b variants were found as well. Furthermore, chromatin immunoprecipitation experiments showed that NFAT1-HDAC4 or NFAT3-HDAC4 complexes might be involved in regulation of PMCA2x splicing variant generation.ConclusionsWe suggest that the influence of NFAT/HDAC on PMCA isoform composition might be important for altered dopamine secretion by PC12 cells.

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“…First, a CsA dose-screening test was conducted to find the appropriate concentration of the drug. Concentrations of 1, 10, 100, and 200 μg/ml were selected based on several reports (4,19,27) and applied to the cell-seeded well plate. The cells were cultured for 24 h, and the cells with cell culture media were harvested for further assay.…”

Section: Methodsmentioning

confidence: 99%

3D-Printed Drug/Cell Carrier Enabling Effective Release of Cyclosporin a for Xenogeneic Cell-Based Therapy

et al. 2015

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Systemic administration of the immunosuppressive drug cyclosporin A (CsA) is frequently associated with a number of side effects; therefore, sometimes it cannot be applied in sufficient dosage after allogeneic or xenogeneic cell transplantation. Local delivery is a possible solution to this problem. We used 3D printing to develop a CsA-loaded 3D drug carrier for the purpose of local and sustained delivery of CsA. The carrier is a hybrid of CsA-poly(lactic-co-glycolic acid) (PLGA) microsphere-loaded hydrogel and a polymeric framework so that external force can be endured under physiological conditions. The expression of cytokines, which are secreted by spleen cells activated by Con A, and which are related to immune rejection, was significantly decreased in vitro by the released CsA from the drug carrier. Drug carriers seeded with xenogeneic cells (human lung fibroblast) were subcutaneously implanted into the BALB/c mouse. As a result, T-cell-mediated rejection was also significantly suppressed for 4 weeks. These results show that the developed 3D drug carrier can be used as an effective xenogeneic cell delivery system with controllable immunosuppressive drugs for cell-based therapy.

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The usage of alternative splice sites in mus musculus synaptotagmin-like 2 gene is modulated by cyclosporin A and FK506 in T-lymphocytes

Cited by 4 publications

References 45 publications

Characterization of a P-Rex1 gene signature in breast cancer cells

Characterization of a P-Rex1 gene signature in breast cancer cells

NFAT1 and NFAT3 Cooperate with HDAC4 during Regulation of Alternative Splicing of PMCA Isoforms in PC12 Cells

3D-Printed Drug/Cell Carrier Enabling Effective Release of Cyclosporin a for Xenogeneic Cell-Based Therapy

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