14-3-3 Integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198-FGFR1-transformed hematopoietic cells.

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Dong S, Kang S, Gu TL, Kardar S, Fu H, Lonial S, Khoury HJ, Khuri F, Chen J

14-3-3 Integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198-FGFR1-transformed hematopoietic cells.

Blood. 2007 Jul 1;110(1):360-9. Epub 2007 Mar 27.

PubMed ID

17389761 [ View in PubMed

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Abstract

Human 8p11 stem cell leukemia/lymphoma syndrome usually presents as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-FGFR1 fusion tyrosine kinase that plays a pathogenic role in hematopoietic transformation. We found that ZNF198-FGFR1 activated both the AKT and mitogen activated protein kinase (MAPK) prosurvival signaling pathways, resulting in elevated phosphorylation of the AKT target FOXO3a at T32 and BAD at S112, respectively. These phosphorylated residues subsequently sequestered the proapoptotic FOXO3a and BAD to 14-3-3 to prevent apoptosis. We used a peptide-based 14-3-3 competitive antagonist, R18, to disrupt 14-3-3-ligand association. Expression of R18 effectively induced apoptosis in hematopoietic Ba/F3 cells transformed by ZNF198-FGFR1 compared with control cells. Moreover, purified recombinant transactivator of transcription (TAT)-conjugated R18 proteins effectively transduced into human leukemia cells and induced significant apoptosis in KG-1a cells expressing FGFR1OP2-FGFR1 fusion tyrosine kinase but not in control HL-60 and Jurkat T cells. Surprisingly, R18 was only able to dissociate FOXO3a, but not BAD as previously proposed, from 14-3-3 binding and induced apoptosis partially through liberation and reactivation of FOXO3a. Our findings suggest that 14-3-3 integrates prosurvival signals in FGFR1 fusion-transformed hematopoietic cells. Disrupting 14-3-3-ligand association may represent an effective therapeutic strategy to treat 8p11 stem cell MPD.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tyrosine	Tyrosine aminotransferase	Protein	Humans	Unknown	Not Available	Details

Polypeptides

Name	UniProt ID
Fibroblast growth factor receptor 1	P11362	Details