Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a life-threatening complication of neurofibromatosis type 1 (NF1). NF1 is caused by mutation in the gene encoding neurofibromin, a negative regulator of Ras signaling. There are no effective pharmacologic therapies for MPNST. To identify new therapeutic approaches targeting this dangerous malignancy, we developed assays in NF1(+/+) and NF1(-/-) MPNST cell lines and in budding yeast lacking the NF1 homologue IRA2 (ira2Δ). Here, we describe UC1, a small molecule that targets NF1(-/-) cell lines and ira2Δ budding yeast. By using yeast genetics, we identified NAB3 as a high-copy suppressor of UC1 sensitivity. NAB3 encodes an RNA binding protein that associates with the C-terminal domain of RNA Pol II and plays a role in the termination of nonpolyadenylated RNA transcripts. Strains with deletion of IRA2 are sensitive to genetic inactivation of NAB3, suggesting an interaction between Ras signaling and Nab3-dependent transcript termination. This work identifies a lead compound and a possible target pathway for NF1-associated MPNST, and shows a novel model system approach to identify and validate target pathways for cancer cells in which NF1 loss drives tumor formation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Cell Line
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Drug Discovery
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Epistasis, Genetic
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GTPase-Activating Proteins / genetics*
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Gene Deletion
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Gene Expression Regulation, Fungal
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Gene Expression Regulation, Neoplastic
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High-Throughput Screening Assays
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Humans
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Nerve Sheath Neoplasms / drug therapy*
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Neurofibromin 1 / genetics*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Protein Kinases / genetics
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Saccharomyces cerevisiae / genetics*
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Saccharomyces cerevisiae Proteins / genetics*
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Saccharomyces cerevisiae Proteins / metabolism
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Sensitivity and Specificity
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Small Molecule Libraries
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Thiourea / analogs & derivatives*
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Thiourea / chemistry
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Thiourea / pharmacology
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Transcription, Genetic
Substances
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(3-(3-bromophenyl)-1-phenylpyrazol-4-yl)methyl carbamimidothioate
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Antineoplastic Agents
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CTDK-I protein complex, S cerevisiae
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GTPase-Activating Proteins
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IRA2 protein, S cerevisiae
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NAB3 protein, S cerevisiae
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Neurofibromin 1
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Nuclear Proteins
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Pyrazoles
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RNA-Binding Proteins
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Saccharomyces cerevisiae Proteins
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Small Molecule Libraries
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Protein Kinases
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Thiourea