Reference

natureMARZONature Medicine 22, 91–96 (2016); PMID: 26692333; doi:10.1038/nm.4013

Authors

Fernando G Osorio, Clara Soria-Valles, Olaya Santiago-Fernández, Teresa Bernal, María Mittelbrunn, Enrique Colado, Francisco Rodríguez, Elena Bonzon-Kulichenko, Jesús Vázquez, Montserrat Porta-de-la-Riva, Julián Cerón, Antonio Fueyo, Juan Li, Anthony R Green, José M P Freije & Carlos López-Otín.

Abstract

AIRAPL (arsenite-inducible RNA-associated protein-like) is an evolutionarily conserved regulator of cellular proteostasis linked to longevity in nematodes, but its biological function in mammals is unknown. We show herein that AIRAPL-deficient mice develop a fully-penetrant myeloproliferative neoplastic process. Proteomic analysis of AIRAPL-deficient mice revealed that this protein exerts its antineoplastic function through the regulation of the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. We demonstrate that AIRAPL interacts with newly synthesized insulin-related growth factor-1 receptor (IGF1R) polypeptides, promoting their ubiquitination and proteasome-mediated degradation. Accordingly, genetic and pharmacological IGF1R inhibitory strategies prevent the hematological disease found in AIRAPL-deficient mice as well as that in mice carrying the Jak2V617F mutation, thereby demonstrating the causal involvement of this pathway in the pathogenesis of myeloproliferative neoplasms. Consistent with its proposed role as a tumor suppressor of myeloid transformation, AIRAPL expression is widely abrogated in human myeloproliferative disorders. Collectively, these findings support the oncogenic relevance of proteostasis deregulation in hematopoietic cells, and they unveil novel therapeutic targets for these frequent hematological neoplasias.

Description

En este trabajo hemos caracterizado el papel de la proteostasis en los procesos de cáncer y envejecimiento a través de la generación de ratones deficientes en la proteína AIRAPL. Así, hemos demostrado que la deficiencia en esta proteína causa síndromes mieloproliferativos en ratones. La función principal de AIRAPL consiste en la regulación negativa del receptor del factor de crecimiento IGF-1 (IGF1R) en el retículo endoplásmico, promoviendo su degradación en el proteasoma. La ausencia de AIRAPL conlleva una desregulación de la señalización de IGF-1, causando transformación mieloide. Estos resultados ponen de manifiesto la relevancia de las alteraciones en la proteostasis en la transformación tumoral, aportando además nuevos marcadores diagnósticos y terapéuticos para este grupo de patologías mieloides.

 

Fotogrupomarzo

 

REFERENCIA DEL GRUPO INVESTIGADOR

El laboratorio dirigido por Carlos López-Otín pertenece al Departamento de Bioquímica y Biología Molecular de la Universidad de Oviedo, y al Instituto Universitario de Oncología del Principado de Asturias (IUOPA). Uno de los principales objetivos del grupo es el estudio de los sistemas proteolíticos implicados en los procesos de cáncer y envejecimiento. Además, el laboratorio de López-Otín ha participado activamente en la secuenciación, anotación y análisis funcional del genoma de la leucemia linfocítica crónica, así como al de distintas especies animales de interés evolutivo y biomédico.

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