The driver of malignancy in KG-1a leukemic cells, FGFR1OP2-FGFR1, encodes an HSP90 addicted oncoprotein.
Cell Signal
; 23(11): 1758-66, 2011 Nov.
Article
en En
| MEDLINE
| ID: mdl-21745565
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Proteínas de Fusión Oncogénica
/
Receptores de Factores de Crecimiento de Fibroblastos
/
Proteínas HSP90 de Choque Térmico
/
Chaperoninas
/
Proteínas de Ciclo Celular
/
Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos
/
Proteínas de Neoplasias
Límite:
Humans
Idioma:
En
Revista:
Cell Signal
Año:
2011
Tipo del documento:
Article
País de afiliación:
Noruega