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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1740-1750 |
| Number of pages | 11 |
| Journal | Molecular cancer therapeutics |
| Volume | 10 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2011 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Discovery of a small molecule targeting IRA2 deletion in budding yeast and neurofibromin loss in malignant peripheral nerve sheath tumor cells. / Wood, Matthew; Rawe, Melissa; Johansson, Gunnar; Pang, Shu; Soderquist, Ryan S.; Patel, Ami V.; Nelson, Sandra; Seibel, William; Ratner, Nancy; Sanchez, Yolanda.
In: Molecular cancer therapeutics, Vol. 10, No. 9, 01.09.2011, p. 1740-1750.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Discovery of a small molecule targeting IRA2 deletion in budding yeast and neurofibromin loss in malignant peripheral nerve sheath tumor cells
AU - Wood, Matthew
AU - Rawe, Melissa
AU - Johansson, Gunnar
AU - Pang, Shu
AU - Soderquist, Ryan S.
AU - Patel, Ami V.
AU - Nelson, Sandra
AU - Seibel, William
AU - Ratner, Nancy
AU - Sanchez, Yolanda
PY - 2011/9/1
Y1 - 2011/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80052735880&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052735880&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-11-0309
DO - 10.1158/1535-7163.MCT-11-0309
M3 - Article
C2 - 21697395
AN - SCOPUS:80052735880
VL - 10
SP - 1740
EP - 1750
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 9
ER -