Ten years of antisense inhibition of brain G-protein-coupled receptor function

Oekelen, Dirk Van; Luyten, Walter; Leysen, Josée E.

doi:10.1016/s0165-0173(03)00153-x

Cited by 24 publications

(19 citation statements)

References 183 publications

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“…Interestingly, in studies of tissues that are terminally differentiated and not undergoing proliferation, such as the central nervous system, RNase H activity is almost undetectable (20). In such cases, antisense targeting of select genes can result in only a partial decrease or even an increase in the level of the target mRNA (20), an event where antisense may function by hybrid-arrested translation resulting in the reduction of the selected protein, as observed in this study. Antisense inhibition of HAS2 in MDA-MB-231 did not alter the expression level of HAS1 or HAS3, not an unexpected finding as the HAS genes are located on separate chromosomes (21).…”

Section: Discussionsupporting

confidence: 56%

“…The lack of protein translation in the presence of mRNA could potentially be due to the mechanistic action by which antisense exerts its effect over gene transcription/ translation in a given cell type. For example, the RNase H-mediated activity, where the resultant RNA-DNA duplexes formed are hydrolyzed by action of endogenous RNase H activity, results in degradation of the target RNA and eventual inhibition of gene expression (20). Interestingly, in studies of tissues that are terminally differentiated and not undergoing proliferation, such as the central nervous system, RNase H activity is almost undetectable (20).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the RNase H-mediated activity, where the resultant RNA-DNA duplexes formed are hydrolyzed by action of endogenous RNase H activity, results in degradation of the target RNA and eventual inhibition of gene expression (20). Interestingly, in studies of tissues that are terminally differentiated and not undergoing proliferation, such as the central nervous system, RNase H activity is almost undetectable (20). In such cases, antisense targeting of select genes can result in only a partial decrease or even an increase in the level of the target mRNA (20), an event where antisense may function by hybrid-arrested translation resulting in the reduction of the selected protein, as observed in this study.…”

Section: Discussionmentioning

confidence: 99%

“…After reaching 50% confluence, cells were grown in thymidine-free culture medium. Cells were harvested by trypsinization at 0, 4,8,12,16,20,24,28,32, and 36 hours followed by fixation in 95% ethanol for 2 hours at 4jC. Cells were pretreated with RNase (100 Ag/mL; Sigma) and 50 Ag/mL propidium iodide (Sigma) for 30 minutes at 37jC before determining the stage of cell cycle stage using a FACSCalibur analytic instrument (Becton Dickinson, San Jose, CA).…”

Section: Methodsmentioning

confidence: 99%

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Antisense-Mediated Suppression of Hyaluronan Synthase 2 Inhibits the Tumorigenesis and Progression of Breast Cancer

et al. 2005

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The progression of several cancers is correlated with the increased synthesis of the glycosaminoglycan, hyaluronan. Hyaluronan is synthesized at the plasma membrane by various isoforms of hyaluronan synthases (HAS). The importance of HAS2 expression in highly invasive breast cancer was characterized by the antisense inhibition of HAS2 (ASHAS2). The effect of HAS2 inhibition on cell proliferation, migration, hyaluronan metabolism, and receptor status was characterized in vitro, whereas the effect on tumorigenicity and metastasis was established in vivo. HAS2 inhibition resulted in a 24-hour lag in proliferation that was concomitant to transient arrest of 79% of the cell population in G 0 -G 1 . Inhibition of HAS2 did not alter the expression of the other HAS isoforms, whereas hyaluronidase (HYAL2) and the hyaluronan receptor, CD44, were significantly down-regulated. ASHAS2 cells accumulated greater amounts of high molecular weight hyaluronan (>10,000 kDa) in the culture medium, whereas mock and parental cells liberated less hyaluronan of three distinct molecular weights (100, 400, and 3,000 kDa). The inhibition of HAS2 in the highly invasive MDA-MB-231 breast cancer cell line inhibited the initiation and progression of primary and secondary tumor formation following s.c. and intracardiac inoculation into nude mice, whereas controls readily established both primary and secondary tumors. The lack of primary and secondary tumor formation was manifested by increased survival times where ASHAS2 animals survived 172% longer than the control animals. Collectively, these unique results strongly implicate the central role of HAS2 in the initiation and progression of breast cancer, potentially highlighting the codependency between HAS2, CD44, and HYAL2 expression. (Cancer Res 2005; 65(14): 6139-50)

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Antisense-Mediated Suppression of Hyaluronan Synthase 2 Inhibits the Tumorigenesis and Progression of Breast Cancer

et al. 2005

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“…A gene-silencing technique was employed to specifically inhibit translation of the C5L2 mRNA in both human (HSF) and mouse (3T3-L1 preadipocyte) cells. The antisense technique involves the transfection of DNA oligomers that are complementary to the target mRNA and, upon binding, inhibit passage of the mRNA through the ribosome (46). Generally, oligonucleotides are designed to different regions of the mRNA of interest, and the most effective are determined empirically.…”

Section: C5l2 Is a Functional Asp Receptormentioning

confidence: 99%

C5L2 Is a Functional Receptor for Acylation-stimulating Protein

Kalant

MacLaren²,

Cui³

et al. 2005

Journal of Biological Chemistry

162

191

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A Quantitative Systems Pharmacology Computer Model for Schizophrenia Efficacy and Extrapyramidal Side Effects

Spiros

Roberts

Geerts

2012

Drug Development Research

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Despite tremendous advances in understanding the neurobiology of schizophrenia, no real therapeutic breakthrough in terms of novel antipsychotics has been made since the serendipitous discovery of chlorpromazine. We describe a computer-based mechanistic disease simulation model of biophysically realistic neurons that captures most of the subcortical neuromodulatory processes important in the pathophysiology of schizophrenia and calibrate this with a large retrospective clinical database for Positive and Negative Symptoms Scale in Schizophrenia (PANSS total) and extrapyramidal symptoms (EPS) liability. Additionally we make this platform more actionable for practical use in central nervous system drug discovery by introducing a synaptic receptor competition model that accurately captures clinical target exposures. The model accounts for threefold more variance than the simple dopamine D2 receptor occupancy rule and is also superior in a number of independent clinical data sets. As such, the model is a first step in a better understanding of the human neurobiology of schizophrenia. Using human pharmacology and a positron emission tomography target engagement study as input, the model can estimate a value for the clinical efficacy on PANSS total and EPS side effect liability for the clinical doses of a new investigative compound. This Quantitative Systems Pharmacology platform, by simulating the effect of co-medications and genotypes in a clinical setting, represents a useful addition to psychiatric drug discovery efforts. Drug Dev Res 73 : 196-213, 2012.

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Ten years of antisense inhibition of brain G-protein-coupled receptor function

Cited by 24 publications

References 183 publications

Antisense-Mediated Suppression of Hyaluronan Synthase 2 Inhibits the Tumorigenesis and Progression of Breast Cancer

Antisense-Mediated Suppression of Hyaluronan Synthase 2 Inhibits the Tumorigenesis and Progression of Breast Cancer

C5L2 Is a Functional Receptor for Acylation-stimulating Protein

A Quantitative Systems Pharmacology Computer Model for Schizophrenia Efficacy and Extrapyramidal Side Effects

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