Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing of RAD51A Pre-mRNA in Normal Human CD4+ T Lymphocytes

Gladilina, Yulia A.; Bey, Lylia; Hilal, Abdullah; Неборак, Е. В.; Blinova, V. G.; Zhdanov, Dmitry

doi:10.3390/ijms23031863

Cited by 4 publications

(5 citation statements)

References 72 publications

(72 reference statements)

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“…Previously, it was shown that exogenous PAs can promote tumor and normal cell proliferation [43] and provide a cytoprotective action for normal fibroblasts [44]. In accordance, we demonstrated the promotion of WI-38 and HepG2 viability after cell incubation with PAs (Figure 4A,B).…”

Section: Discussionsupporting

confidence: 89%

Anticancer Cytotoxic Activity of Bispidine Derivatives Associated with the Increasing Catabolism of Polyamines

et al. 2022

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Polyamine (PA) catabolism is often reduced in cancer cells. The activation of this metabolic pathway produces cytotoxic substances that might cause apoptosis in cancer cells. Chemical compounds able to restore the level of PA catabolism in tumors could become potential antineoplastic agents. The search for activators of PA catabolism among bicyclononan-9-ones is a promising strategy for drug development. The aim of the study was to evaluate the biological activity of new 3,7-diazabicyclo[3.3.1]nonan-9-one derivatives that have antiproliferative properties by accelerating PA catabolism. Eight bispidine derivatives were synthetized and demonstrated the ability to activate PA catabolism in regenerating rat liver homogenates. However, only three of them demonstrated a potent ability to decrease the viability of cancer cells in the MTT assay. Compounds 4c and 4e could induce apoptosis more effectively in cancer HepG2 cells rather than in normal WI-38 fibroblasts. The lead compound 4e could significantly enhance cancer cell death, but not the death of normal cells if PAs were added to the cell culture media. Thus, the bispidine derivative 4e 3-(3-methoxypropyl)-7-[3-(1H-piperazin-1-yl)ethyl]-3,7-diazabicyclo[3.3.1]nonane could become a potential anticancer drug substance whose mechanism relies on the induction of PA catabolism in cancer cells.

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Section: Discussionsupporting

confidence: 89%

Anticancer Cytotoxic Activity of Bispidine Derivatives Associated with the Increasing Catabolism of Polyamines

et al. 2022

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“…Base-pairing to target pre-mRNA blocks the binding of SR proteins to their binding sites, leading to the retention of associated exons and the inclusion of them into mature mRNA. The modulation of cellular functions by SSOs has been shown by us in several previous studies [34,80,81]. Using SSOs targeting sensitive cis-elements on exon 2 and exon 7, we produced Tregs with selective expression of FL FoxP3 (Figure 2).…”

Section: Discussionmentioning

confidence: 79%

Induction of FoxP3 Pre-mRNA Alternative Splicing to Enhance the Suppressive Activity of Regulatory T Cells from Amyotrophic Lateral Sclerosis Patients

Zhdanov,

Gladilina,

Blinova

et al. 2024

Biomedicines

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Forkhead box protein 3 (FoxP3) is a key transcription factor responsible for the development, maturation, and function of regulatory T cells (Tregs). The FoxP3 pre-mRNA is subject to alternative splicing, resulting in the translation of multiple splice variants. We have shown that Tregs from patients with amyotrophic lateral sclerosis (ALS) have reduced expression of full-length (FL) FoxP3, while other truncated splice variants are expressed predominantly. A correlation was observed between the reduced number of Tregs in the peripheral blood of ALS patients, reduced total FoxP3 mRNA, and reduced mRNA of its FL splice variant. Induction of FL FoxP3 was achieved using splice-switching oligonucleotides capable of base pairing with FoxP3 pre-mRNA and selectively modulating the inclusion of exons 2 and 7 in the mature mRNA. Selective expression of FL FoxP3 resulted in the induction of CD127low, CD152, and Helios-positive cells, while the cell markers CD4 and CD25 were not altered. Such Tregs had an increased proliferative activity and a higher frequency of cell divisions per day. The increased suppressive activity of Tregs with the induced FL FoxP3 splice variant was associated with the increased synthesis of the pro-apoptotic granzymes A and B, and perforin, IL-10, and IL-35, which are responsible for contact-independent suppression, and with the increased ability to suppress telomerase in target cells. The upregulation of Treg suppressive and proliferative activity using splice-switching oligonucleotides to induce the predominant expression of the FoxP3 FL variant is a promising approach for regenerative cell therapy in Treg-associated diseases.

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“…To modulate exon 2 and exon 7 alternative splicing in Tregs and to create a Treg cell line expressing only one of four possible FoxP3 splice variants, we created 36-mer splice-switching oligonucleotides (SSOs). They could base-pair to splicing regulatory sequences and induce deletion ( Figure 3 A,B) or retention of exon 2 or of exon 7 ( Figure 4 A,B) [ 31 , 32 , 33 ]. Tregs from four HDs (donors 9, 10, 11, and 12) were transfected with each single oligonucleotide, and the expression of FoxP3 splice variants was examined four days after transfection.…”

Section: Resultsmentioning

confidence: 99%

“…Modulation of pre-mRNA AS by SSO targeting splicing regulatory cis -elements has been shown by us in several studies on other objects [ 21 , 33 , 71 ], and we used this approach to induce a single FoxP3 splice variant in Tregs. As expected, the use of a single SSO inducing only one exon (2 or 7, Figure 3 and Figure 4 ) insertion or deletion did not allow us to obtain cells with only one splice variant.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Suppressive Activity and Proliferation of Human Regulatory T Cells by Splice-Switching Oligonucleotides Targeting FoxP3 Pre-mRNA

Blinova,

Gladilina,

Abramova

et al. 2023

Cells

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The maturation, development, and function of regulatory T cells (Tregs) are under the control of the crucial transcription factor Forkhead Box Protein 3 (FoxP3). Through alternative splicing, the human FoxP3 gene produces four different splice variants: a full-length variant (FL) and truncated variants with deletions of each of exons 2 (∆2 variant) or 7 (∆7 variant) or a deletion of both exons (∆2∆7 variant). Their involvement in the biology of Tregs as well as their association with autoimmune diseases remains to be clarified. The aim of this work was to induce a single FoxP3 splice variant in human Tregs by splice switching oligonucleotides and to monitor their phenotype and proliferative and suppressive activity. We demonstrated that Tregs from peripheral blood from patients with multiple sclerosis preferentially expressed truncated splice variants, while the FL variant was the major variant in healthy donors. Tregs with induced expression of truncated FoxP3 splice variants demonstrated lower suppressive activity than those expressing FL variants. Reduced suppression was associated with the decreased expression of Treg-associated suppressive surface molecules and the production of cytokines. The deletion of exons 2 and/or 7 also reduced the cell proliferation rate. The results of this study show an association between FoxP3 splice variants and Treg function and proliferation. The modulation of Treg suppressive activity by the induction of the FoxP3 FL variant can become a promising strategy for regenerative immunotherapy.

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Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing of RAD51A Pre-mRNA in Normal Human CD4+ T Lymphocytes

Cited by 4 publications

References 72 publications

Anticancer Cytotoxic Activity of Bispidine Derivatives Associated with the Increasing Catabolism of Polyamines

Anticancer Cytotoxic Activity of Bispidine Derivatives Associated with the Increasing Catabolism of Polyamines

Induction of FoxP3 Pre-mRNA Alternative Splicing to Enhance the Suppressive Activity of Regulatory T Cells from Amyotrophic Lateral Sclerosis Patients

Modulation of Suppressive Activity and Proliferation of Human Regulatory T Cells by Splice-Switching Oligonucleotides Targeting FoxP3 Pre-mRNA

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