Browsing by Subject "Cell cycle and cell division"

Now showing 1 - 4 of 4
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    Open Access
    Accumulation of splice variants and transcripts in response to PI3K inhibition in T cells
    (Public Library of Science, 2013) Riedel, Alice; Mofolo, Boitumelo; Avota, Elita; Schneider-Schaulies, Sibylle; Meintjes, Ayton; Mulder, Nicola; Kneitz, Susanne
    BACKGROUND: Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA. Hypothesis Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing. METHODS: To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression. RESULTS: Applying our algorithm to the data, 9% of the genes were assigned as AS, while only 3% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry. CONCLUSIONS: PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.
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    Growth of HIV-exposed uninfected infants in the first 6 months of life in South Africa: The IeDEA-SA collaboration
    (Public Library of Science, 2016) Morden, Erna; Technau, Karl-Günter; Giddy, Janet; Maxwell, Nicola; Keiser, Olivia; Davies, Mary-Ann
    BACKGROUND: HIV-exposed uninfected (HEU) infants are a growing population in sub-Saharan Africa especially with the increasing coverage of more effective prevention of mother-to-child transmission (PMTCT) antiretroviral therapy regimens. This study describes the characteristics of South African HEU infants, investigates factors impacting birth weight and assesses their growth within the first 28 weeks of life. METHODS: This is a retrospective cohort based on routine clinical data from two South African PMTCT programmes. Data were collected between 2007 and 2013. Linear regression assessed factors affecting birth weight-for-age z-scores (WAZ) while growth (longitudinal WAZ) was assessed using mixed effects models. RESULTS: We assessed the growth of 2621 HEU infants (median birth WAZ was -0.65 (IQR -1.46; 0.0) and 51% were male). The feeding modalities practised were as follows: 0.5% exclusive breastfeeding, 7.9% breastfeeding with unknown exclusivity, 0.08% mixed breastfeeding and 89.2% formula feeding. Mothers with CD4 <200 cells/μl delivered infants with a lower birth WAZ (adjusted ß -0.253 [95% CI -0.043; -0.072], p = 0.006) compared to mothers with aCD4 ≥500 cells/μl. Similarly, mothers who did not receive antiretroviral drugs delivered infants with a lower birth WAZ (adjusted ß -0.39 [95% CI -0.67; -0.11], p = 0.007) compared to mothers who received antenatal antiretrovirals. Infants with a birth weight <2 500g (ß 0.070 [95% CI 0.061; 0.078], p <0.0001) experienced faster growth within the first 28 weeks of life compared to infants with a birth weight ≥2 500g. Infants with any breastfeeding exposure experienced slower longitudinal growth compared to formula fed infants (adjusted ß -0.012 [95% CI 0.021; -0.003], p = 0.011). CONCLUSION: Less severe maternal disease and the use of antiretrovirals positively impacts birth weight in this cohort of South African HEU infants. Formula feeding was common with breastfed infants experiencing marginally slower longitudinal growth.
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    p53 requires the stress sensor USF1 to direct appropriate cell fate decision
    (Public Library of Science, 2014) Bouafia, Amine; Corre, Sébastien; Gilot, David; Mouchet, Nicolas; Prince, Sharon; Galibert, Marie-Dominique
    Genomic instability is a major hallmark of cancer. To maintain genomic integrity, cells are equipped with dedicated sensors to monitor DNA repair or to force damaged cells into death programs. The tumor suppressor p53 is central in this process. Here, we report that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) coordinates p53 function in making proper cell fate decisions. USF1 stabilizes the p53 protein and promotes a transient cell cycle arrest, in the presence of DNA damage. Thus, cell proliferation is maintained inappropriately in Usf1 KO mice and in USF1-deficient melanoma cells challenged by genotoxic stress. We further demonstrate that the loss of USF1 compromises p53 stability by enhancing p53-MDM2 complex formation and MDM2-mediated degradation of p53. In USF1-deficient cells, the level of p53 can be restored by the re-expression of full-length USF1 protein similarly to what is observed using Nutlin-3, a specific inhibitor that prevents p53-MDM2 interaction. Consistent with a new function for USF1, a USF1 truncated protein lacking its DNA-binding and transactivation domains can also restore the induction and activity of p53. These findings establish that p53 function requires the ubiquitous stress sensor USF1 for appropriate cell fate decisions in response to DNA-damage. They underscore the new role of USF1 and give new clues of how p53 loss of function can occur in any cell type. Finally, these findings are of clinical relevance because they provide new therapeutic prospects in stabilizing and reactivating the p53 pathway.
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    SB225002 induces cell death and cell cycle arrest in acute lymphoblastic leukemia cells through the activation of GLIPR1
    (Public Library of Science, 2015) De Vasconcellos, Jaíra Ferreira; Laranjeira, Angelo Brunelli Albertoni; Leal, Paulo C; Bhasin, Manoj K; Zenatti, Priscila Pini; Nunes, Ricardo J; Yunes, Rosendo A; Nowill, Alexandre E; Libermann, Towia A; Zerbini, Luiz Fernando; Yunes, José Andrés
    Acute Lymphoblastic Leukemia (ALL) is the most frequent childhood malignancy. In the effort to find new anti-leukemic agents, we evaluated the small drug SB225002 (N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea). Although initially described as a selective antagonist of CXCR2, later studies have identified other cellular targets for SB225002, with potential medicinal use in cancer. We found that SB225002 has a significant pro-apoptotic effect against both B- and T-ALL cell lines. Cell cycle analysis demonstrated that treatment with SB225002 induces G2-M cell cycle arrest. Transcriptional profiling revealed that SB225002-mediated apoptosis triggered a transcriptional program typical of tubulin binding agents. Network analysis revealed the activation of genes linked to the JUN and p53 pathways and inhibition of genes linked to the TNF pathway. Early cellular effects activated by SB225002 included the up-regulation of GLIPR1 , a p53-target gene shown to have pro-apoptotic activities in prostate and bladder cancer. Silencing of GLIPR1 in B- and T-ALL cell lines resulted in increased resistance to SB225002. Although SB225002 promoted ROS increase in ALL cells, antioxidant N-Acetyl Cysteine pre-treatment only modestly attenuated cell death, implying that the pro-apoptotic effects of SB225002 are not exclusively mediated by ROS. Moreover, GLIPR1 silencing resulted in increased ROS levels both in untreated and SB225002-treated cells. In conclusion, SB225002 induces cell cycle arrest and apoptosis in different B- and T-ALL cell lines. Inhibition of tubulin function with concurrent activation of the p53 pathway, in particular, its downstream target GLIPR1 , seems to underlie the anti-leukemic effect of SB225002.