Wood M, Rawe M, Johansson G, Pang S, Soderquist RS, Patel AV, Nelson S, Seibel W, Ratner N, Sanchez Y

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 ...

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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. 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 non-polyadenylated 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 demonstrates a novel model system approach to identify and validate target pathways for cancer cells in which NF1 loss drives tumor formation.

Date: Jun. 22, 2011

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