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Justesen, Jeannette; Stenderup, Karin; Ebbesen, E.N.; Mosekilde, Li.; Steiniche, Torben; Kassem, Moustapha

doi:10.1023/a:1011513223894

Cited by 739 publications

(340 citation statements)

References 37 publications

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“…Because PI in general show a high degree of protein binding (for LPV, up to 99% of the inhibitor are bound to serum protein), this corresponds to available protein-free inhibitor concentrations in the low nanomolar range (summarized in Ref. 39). Furthermore, drug levels in clinically relevant HIV reservoirs can differ from those reflected in the plasma concentration.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Gag Processing Intermediates Trans-dominantly Interfere with HIV-1 Infectivity

Müller

Anders

Akiyama

et al. 2009

Journal of Biological Chemistry

100

140

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Protease inhibitors (PI) act by blocking human immunodeficiency virus (HIV) polyprotein processing, but there is no direct quantitative correlation between the degree of impairment of Gag processing and virion infectivity at low PI concentrations.To analyze the consequences of partial processing, virus particles were produced in the presence of limiting PI concentrations or by co-transfection of wild-type proviral plasmids with constructs carrying mutations in one or more cleavage sites. Low PI concentrations caused subtle changes in polyprotein processing associated with a pronounced reduction of particle infectivity. Dissection of individual stages of viral entry indicated a block in accumulation of reverse transcriptase products, whereas virus entry, enzymatic reverse transcriptase activity, and replication steps following reverse transcription were not affected. Co-expression of low amounts of partially processed forms of Gag together with wild-type HIV generally exerted a trans-dominant effect, which was most prominent for a construct carrying mutations at both cleavage sites flanking the CA domain. Interestingly, co-expression of low amounts of Gag mutated at the CA-SP1 cleavage site also affected processing activity at this site in the wild-type virus. The results indicate that low amounts (<5%) of Gag processing intermediates can display a trans-dominant effect on HIV particle maturation, with the maturation cleavage between CA and SP1 being of particular importance. These effects are likely to be important for the strong activity of PI at concentrations achieved in vivo and also bear relevance for the mechanism of action of the antiviral drug bevirimat.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Gag Processing Intermediates Trans-dominantly Interfere with HIV-1 Infectivity

Müller

Anders

Akiyama

et al. 2009

Journal of Biological Chemistry

100

140

View full text Add to dashboard Cite

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“…osteoporosis, glucocorticoid, or glitazone therapy) (52). Because osteoblasts and adipocytes arise from MSC in the bone marrow microenvironment, understanding the "switching mechanisms" between osteoblast versus adipocyte differentiation can provide novel therapeutic targets for enhancing bone formation (52,53). Previous studies have identified some factors that play a role in the switching mechanism.…”

Section: T253mentioning

confidence: 99%

Tumor Necrosis Factor Receptor Superfamily Member 19 (TNFRSF19) Regulates Differentiation Fate of Human Mesenchymal (Stromal) Stem Cells through Canonical Wnt Signaling and C/EBP

Qiu

Andersen

et al. 2010

Journal of Biological Chemistry

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Mechanisms controlling human multipotent mesenchymal (stromal) stem cell (hMSC) differentiation into osteoblasts or adipocytes are poorly understood. We have previously demonstrated that Wnt signaling in hMSC enhanced osteoblast differentiation and inhibited adipogenesis by comparing two hMSC cell lines overexpressing mutated forms of the Wnt co-receptor LRP5: T253I (hMSC-LRP5 T253 ) and T244M (hMSC-LRP5 T244 ) conducting high and low level of Wnt signaling, respectively. To explore the underlying molecular mechanisms, we compared gene expression profiles of hMSC-LRP5 T253 and hMSC-LRP5 T244 treated with Wnt3a using whole genome expression microarrays and found that TNFRSF19 is differentially up-regulated between the two cells lines. Bioinformatic analysis and dual luciferase assay of its promoter revealed that TNFRSF19 transcript 2 (TNFRSF19.2) is a target of canonical Wnt signaling. Knocking down TNFRSF19 in hMSC-LRP5 T253 cells decreased Wnt3a-induced osteoblast differentiation marker alkaline phosphate activity and its overexpression in hMSC-LRP5 T244 cells increased alkaline phosphate activity. In addition, TNFRSF19 was negatively regulated by adipogenic transcription factor CCAAT/enhancer-binding proteins (C/EBP). Knocking down TNFRSF19 in hMSC-LRP5 T253 cells or its overexpression in hMSC-LRP5 T244 cells significantly increased or decreased adipogenesis, respectively. In conclusion, we revealed a novel function of TNFRSF19 as a factor mediating differentiation signals that determine the hMSC differentiating fate into osteoblasts or adipocytes.

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“…It has been suggested that the osteogenic and adipogenic differentiation of hMSCs are two inverse processes, with one process inhibiting the other (36). Furthermore, in osteoporotic patients, the number of adipocytes was increased in the marrow, implying a change of cell fate disposition from osteoblast lineage to adipocyte lineage (37,38). We therefore examined the effect of our hit siRNAs on adipogenic differentiation of hMSCs by combined treatment with an adipogenic inducing mixture [100 g/ml 3-isobutyl-1-methylxanthine (IBMX)/1 M dexamethasone/10 g/ml insulin].…”

Section: High-throughput Sirna Screen In Hmscsmentioning

confidence: 99%

A high-throughput siRNA library screen identifies osteogenic suppressors in human mesenchymal stem cells

Zhao

Ding

2007

Proc. Natl. Acad. Sci. U.S.A.

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Tissue-specific (or adult) stem/progenitor cells are regarded as the source for normal tissue homeostasis and tissue repair. They also provide tremendous promise for regenerative medicine because of their capacity to proliferate and differentiate into a variety of mature cell types. Human mesenchymal stem cells (hMSCs) can differentiate into osteocytes, adipocytes, chondrocytes, muscle cells, and neurons. However, the molecular mechanisms underlying these differentiation processes are poorly understood. We screened a synthetic siRNA library targeting 5,000 human genes to identify the endogenous repressors of osteogenic specification, which when silenced could initiate differentiation of hMSCs into osteoblasts. This screen yielded 53 candidate suppressors, and 12 of those were further confirmed for their dynamic roles in suppressing osteogenic specification in hMSCs. Furthermore, cAMP was identified to play opposing roles in osteogenesis vs. adipogenesis. This study provides a basis for further elucidation of the genetic network controlling osteogenesis and, potentially, the molecular rationale for treating bone diseases.adipogenic differentiation ͉ osteogenic differentiation ͉ high-throughput RNAi screen

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Cited by 739 publications

References 37 publications

HIV-1 Gag Processing Intermediates Trans-dominantly Interfere with HIV-1 Infectivity

HIV-1 Gag Processing Intermediates Trans-dominantly Interfere with HIV-1 Infectivity

Tumor Necrosis Factor Receptor Superfamily Member 19 (TNFRSF19) Regulates Differentiation Fate of Human Mesenchymal (Stromal) Stem Cells through Canonical Wnt Signaling and C/EBP

A high-throughput siRNA library screen identifies osteogenic suppressors in human mesenchymal stem cells

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