RESUMEN
Approximately a third of patients with Langerhans cell histiocytosis (LCH) experience recurrence of disease. Genomic analysis has revealed that this condition is often driven by oncogenic mutations in the MAP kinase (MAPK) pathway, and agents that target components of this pathway have been explored as a second-line treatment for LCH. Here, we examine 2 pediatric patients with LCH and confirmed but rarely reported MAPK pathway mutations treated with trametinib, a MAP2K inhibitor approved to treat several cancers with a BRAFV600E mutation. Each patient achieved or maintained complete resolution of disease and remain on the drug with no adverse effects.
Asunto(s)
Histiocitosis de Células de Langerhans , Sistema de Señalización de MAP Quinasas , Humanos , Niño , Sistema de Señalización de MAP Quinasas/genética , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Histiocitosis de Células de Langerhans/genética , Piridonas/uso terapéutico , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutación , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
During eukaryotic translation initiation, eIF3 binds the solvent-accessible side of the 40S ribosome and recruits the gate-keeper protein eIF1 and eIF5 to the decoding center. This is largely mediated by the N-terminal domain (NTD) of eIF3c, which can be divided into three parts: 3c0, 3c1, and 3c2. The N-terminal part, 3c0, binds eIF5 strongly but only weakly to the ribosome-binding surface of eIF1, whereas 3c1 and 3c2 form a stoichiometric complex with eIF1. 3c1 contacts eIF1 through Arg-53 and Leu-96, while 3c2 faces 40S protein uS15/S13, to anchor eIF1 to the scanning pre-initiation complex (PIC). We propose that the 3c0:eIF1 interaction diminishes eIF1 binding to the 40S, whereas 3c0:eIF5 interaction stabilizes the scanning PIC by precluding this inhibitory interaction. Upon start codon recognition, interactions involving eIF5, and ultimately 3c0:eIF1 association, facilitate eIF1 release. Our results reveal intricate molecular interactions within the PIC, programmed for rapid scanning-arrest at the start codon.
Asunto(s)
Factor 3 de Iniciación Eucariótica/química , Factor 3 de Iniciación Eucariótica/metabolismo , Factor 5 Eucariótico de Iniciación/metabolismo , Iniciación de la Cadena Peptídica Traduccional , ARN Mensajero/metabolismo , Ribosomas/química , Ribosomas/metabolismo , Saccharomyces cerevisiae/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Factor 1 Eucariótico de Iniciación/metabolismo , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Mutación/genética , Unión Proteica , Subunidades de Proteína/metabolismo , ARN Mensajero/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMEN
ATF4 is a pro-oncogenic transcription factor whose translation is activated by eIF2 phosphorylation through delayed re-initiation involving two uORFs in the mRNA leader. However, in yeast, the effect of eIF2 phosphorylation can be mimicked by eIF5 overexpression, which turns eIF5 into translational inhibitor, thereby promoting translation of GCN4, the yeast ATF4 equivalent. Furthermore, regulatory protein termed eIF5-mimic protein (5MP) can bind eIF2 and inhibit general translation. Here, we show that 5MP1 overexpression in human cells leads to strong formation of 5MP1:eIF2 complex, nearly comparable to that of eIF5:eIF2 complex produced by eIF5 overexpression. Overexpression of eIF5, 5MP1 and 5MP2, the second human paralog, promotes ATF4 expression in certain types of human cells including fibrosarcoma. 5MP overexpression also induces ATF4 expression in Drosophila The knockdown of 5MP1 in fibrosarcoma attenuates ATF4 expression and its tumor formation on nude mice. Since 5MP2 is overproduced in salivary mucoepidermoid carcinoma, we propose that overexpression of eIF5 and 5MP induces translation of ATF4 and potentially other genes with uORFs in their mRNA leaders through delayed re-initiation, thereby enhancing the survival of normal and cancer cells under stress conditions.