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

ArticleinBlood 110(1):360-9 · July 2007with5 Reads
DOI: 10.1182/blood-2006-12-065615 · Source: PubMed
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.
    • " Nuclear export of FOXOs can be blocked by inhibitors of the 14-3-3 chaperone protein family and related exportins. Dong et al. (2007) demonstrated that treatment of an in vitro leukemia cell-model with the peptide R18, downregulated 14-3-3 protein expression, which in turn leads to increased nuclear accumulation of FOXO3A; and restored transcription of its anti-proliferative targets p27 kip1 and Bim. More recently, Mori et al. (2014) have developed novel compounds tha"
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    • "Different 14-3-3 isoforms have been implicated in the regulation of many intracellular signaling processes including mitogenesis, the DNA damage checkpoint, cell cycle control, and apoptosis via their ability to bind specific phospho-serine/threoninecontaining motifs on the target protein [3]. Furthermore, the 14-3-3 proteins have been shown to regulate mitogenactivated protein kinase (MAPK) signaling by influencing the binding of Ras, Raf, and MEK, which plays a critical role in regulating tumor growth456. Compared to other 14-3-3 isoforms, few studies on 14-3-3θ have been conducted, and the studies that have evaluated the role of 14-3-3θ have all focused on cell survival and apoptosis [7, 8]. Deletion of 14-3-3θ in mice leads to embryonic lethality, and the cardiocytes of 14-3- 3θ+/-mice are resistant to cardiomyocyte apoptosis [9]. "
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    • "An emerging role for 14-3-3f as an effector of prosurvival signaling is suggested in part by the large number of 14-3- 3f binding proteins involved in apoptosis. 14-3-3 binding inactivates numerous pro-apoptotic proteins, such as the BH3 domain-containing proteins (BAD, BAX, etc.) by sequestering them from their sites of action [45,46,47,48,49,50]. p53 is an important transcriptional regulator of BH3 domain-containing proteins and plays a crucial role in apoptosis by promoting the synthesis of these proteins [25,26]. "
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