Abstract |
The KG-1a cell line is developed from a human stem cell myeloproliferative neoplasm as the result of intragenic disruption and a chromosomal translocation of the FGFR1 gene and the FGFR1OP2 gene encoding a protein of unknown function called FOP2 ( FGFR1 Oncogene Partner 2). The resulting fusion protein FOP2-FGFR1 is soluble and has constitutive tyrosine kinase activity. Since the heat shock protein HSP90 and its co-chaperone CDC37 have been shown to stabilize many oncogenic proteins, we investigated the requirement for HSP90 or HSP90-CDC37 assistance to maintain the stability or activity of FOP2-FGFR1 expressed in KG-1a cells. We found that HSP90-CDC37 forms a permanent complex with FOP2-FGFR1. This results in protection against degradation of FOP2-FGFR1 and holds the oncoprotein in a permanently active conformation. Inhibition of HSP90 or depletion of CDC37 or heat shock factor 1 (HSF1) reduced the expression level of FOP2-FGFR1 and was sufficient to block the oncoprotein induced proliferation of KG-1a cells. We conclude that the driver of malignancy in KG-1a leukemic cells, FOP2-FGFR1, is an HSP90 addicted oncoprotein. This provides a rationale for the therapeutic use of HSP90 inhibitors in myeloid leukemias that contain FGFR fusion proteins.
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Authors | Yixin Jin, Yan Zhen, Ellen Margrethe Haugsten, Antoni Wiedlocha |
Journal | Cellular signalling
(Cell Signal)
Vol. 23
Issue 11
Pg. 1758-66
(Nov 2011)
ISSN: 1873-3913 [Electronic] England |
PMID | 21745565
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 Elsevier Inc. All rights reserved. |
Chemical References |
- CDC37 protein, human
- Cell Cycle Proteins
- FOP-FGFR1 fusion protein, human
- HSP90 Heat-Shock Proteins
- Neoplasm Proteins
- Oncogene Proteins, Fusion
- Receptors, Fibroblast Growth Factor
- Receptor, Fibroblast Growth Factor, Type 1
- Chaperonins
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Topics |
- Blotting, Western
- Cell Cycle Proteins
(genetics, metabolism)
- Cell Line, Tumor
- Cell Proliferation
- Chaperonins
(genetics, metabolism)
- HSP90 Heat-Shock Proteins
(genetics, metabolism)
- Humans
- Immunoprecipitation
- Leukemia, Myeloid
(genetics)
- Neoplasm Proteins
(genetics, metabolism)
- Oncogene Proteins, Fusion
(genetics, metabolism)
- Phosphorylation
- Protein Binding
- Protein Conformation
- Receptor, Fibroblast Growth Factor, Type 1
(genetics, metabolism)
- Receptors, Fibroblast Growth Factor
(genetics, metabolism)
- Signal Transduction
(genetics)
- Translocation, Genetic
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