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.

Descárgate este artículo aquí.

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Fisher Scientific Prize which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma

01-12-2017

CIC (also known as Capicua) is a transcriptional repressor negatively regulated by RAS/MAPK signaling. Whereas the functions of Cic have been well characterized in Drosophila, little is known about its...

Read more

Physical proximity of chromatin to nuclear pores prevents harmful R loop accumulation contributing to maintain genome stability

01-11-2017

During transcription, the mRNA may hybridize with DNA, forming an R loop, which can be physiological or pathological, constituting in this case a source of genomic instability. To understand the...

Read more

Whi7 is an unstable cell-cycle repressor of the Start transcriptional program

01-10-2017

Start is the main decision point in eukaryotic cell cycle in which cells commit to a new round of cell division. It involves the irreversible activation of a transcriptional program...

Read more

CTCF orchestrates the germinal centre transcriptional program and prevents premature plasma cell differentiation

01-09-2017

In germinal centres (GC) mature B cells undergo intense proliferation and immunoglobulin gene modification before they differentiate into memory B cells or long-lived plasma cells (PC). GC B-cell-to-PC transition involves...

Read more

Catalytic Cycle of the N-Acetylglucosaminidase NagZ from Pseudomonas aeruginosa

01-08-2017

The N-acetylglucosaminidase NagZ of Pseudomonas aeruginosa catalyzes the first cytoplasmic step in recycling of muropeptides, cell-wall-derived natural products. This reaction regulates gene expression for the β-lactam resistance enzyme, β-lactamase. The...

Read more

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice.

01-07-2017

CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits...

Read more

Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver

01-06-2017

The type 2 immune response controls helminth infection and maintains tissue homeostasis but can lead to allergy and fibrosis if not adequately regulated. We have discovered local tissue-specific amplifiers of...

Read more

Programmed mitophagy is essential for the glycolytic switch during cell differentiation

01-05-2017

Retinal ganglion cells (RGCs) are the sole projecting neurons of the retina and their axons form the optic nerve. Here, we show that embryogenesis-associated mouse RGC differentiation depends on mitophagy...

Read more

Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes

01-04-2017

The Bcl-2 (B-cell lymphoma 2) protein Bax (Bcl-2 associated X, apoptosis regulator) can commit cells to apoptosis via outer mitochondrial membrane permeabilization. Bax activity is controlled in healthy cells by...

Read more

Histone chaperone activity of Arabidopsis thaliana NRP1 is blocked by cytochrome c

01-03-2017

Higher-order plants and mammals use similar mechanisms to repair and tolerate oxidative DNA damage. Most studies on the DNA repair process have focused on yeast and mammals, in which histone...

Read more

Protector Members