Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling

Osorio, Fernando G.; Soria‐Valles, Clara; Santiago‐Fernández, Olaya; Bernal, Teresa; Mittelbrunn, Marı́a; Colado, Enrique; Rodríguez, Francisco; Bonzón-Kulichenko, Elena; Vázquez, Jesús; Porta-de-la-Riva, Montserrat; Cerón, Julián; Fueyo, Antonio; Li, Juan; Green, Andrew; Freije, José M.P.

doi:10.1038/nm.4013

Cited by 43 publications

(52 citation statements)

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“…In support of this claim, a recent study showed that activation of Janus kinase 2 (JAK2) signaling associated with myeloproliferative neoplasms (MPNs) resulted in reduced expression of proteostasis component AIRAPL (arsenite-inducible RNA-associated protein-like) and led to increased insulin/insulin-like growth factor 1 (IGF1R) stability and disrupted hematopoietic differentiation [62]. Thus, changes in expression of proteostasis components can result in modulated folding or degradation of cellular factors, such as signaling proteins that, in turn, can lead to alterations in differentiation.…”

Section: Discussionmentioning

confidence: 99%

A Differentiation Transcription Factor Establishes Muscle-Specific Proteostasis in Caenorhabditis elegans

et al. 2016

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Safeguarding the proteome is central to the health of the cell. In multi-cellular organisms, the composition of the proteome, and by extension, protein-folding requirements, varies between cells. In agreement, chaperone network composition differs between tissues. Here, we ask how chaperone expression is regulated in a cell type-specific manner and whether cellular differentiation affects chaperone expression. Our bioinformatics analyses show that the myogenic transcription factor HLH-1 (MyoD) can bind to the promoters of chaperone genes expressed or required for the folding of muscle proteins. To test this experimentally, we employed HLH-1 myogenic potential to genetically modulate cellular differentiation of Caenorhabditis elegans embryonic cells by ectopically expressing HLH-1 in all cells of the embryo and monitoring chaperone expression. We found that HLH-1-dependent myogenic conversion specifically induced the expression of putative HLH-1-regulated chaperones in differentiating muscle cells. Moreover, disrupting the putative HLH-1-binding sites on ubiquitously expressed daf-21(Hsp90) and muscle-enriched hsp-12.2(sHsp) promoters abolished their myogenic-dependent expression. Disrupting HLH-1 function in muscle cells reduced the expression of putative HLH-1-regulated chaperones and compromised muscle proteostasis during and after embryogenesis. In turn, we found that modulating the expression of muscle chaperones disrupted the folding and assembly of muscle proteins and thus, myogenesis. Moreover, muscle-specific over-expression of the DNAJB6 homolog DNJ-24, a limb-girdle muscular dystrophy-associated chaperone, disrupted the muscle chaperone network and exposed synthetic motility defects. We propose that cellular differentiation could establish a proteostasis network dedicated to the folding and maintenance of the muscle proteome. Such cell-specific proteostasis networks can explain the selective vulnerability that many diseases of protein misfolding exhibit even when the misfolded protein is ubiquitously expressed.

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Section: Discussionmentioning

confidence: 99%

A Differentiation Transcription Factor Establishes Muscle-Specific Proteostasis in Caenorhabditis elegans

et al. 2016

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“…A recent study demonstrated that AIRAPL-deficient mice develop a fully penetrant MPN-like disease [174]. Further analysis of the mechanisms underlying these findings demonstrated that AIRAPL promotes the ubiquitination and proteasome degradation of newly synthesized IGF-IR receptor polypeptides, which leads to apoptotic cell death.…”

Section: Role Of Igf-ir Signaling In Hematological Malignanciesmentioning

confidence: 99%

“…The lack of AIRAPL and its inhibitory effects on IGF-IR signaling and apoptosis, in reverse, lead to the development of MPN. This intriguing idea was further supported by: (1) targeting IGF-IR prevented MPN in AIRAPL-deficient mice as well as in mice carrying the Jak2 V617F mutation; and (2) the expression of AIRAPL was found to be commonly lacking in human MPN samples [174]. …”

Section: Role Of Igf-ir Signaling In Hematological Malignanciesmentioning

confidence: 99%

Type I insulin-like growth factor receptor signaling in hematological malignancies

et al. 2016

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The insulin-like growth factor (IGF) signaling system plays key roles in the establishment and progression of different types of cancer. In agreement with this idea, substantial evidence has shown that the type I IGF receptor (IGF-IR) and its primary ligand IGF-I are important for maintaining the survival of malignant cells of hematopoietic origin. In this review, we discuss current understanding of the role of IGF-IR signaling in cancer with a focus on the hematological neoplasms. We also address the emergence of IGF-IR as a potential therapeutic target for the treatment of different types of cancer including plasma cell myeloma, leukemia, and lymphoma.

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“…Determination of nitrite production in macrophages was performed using Griess Reagent (Molecular Probes) following manufacturer instructions. Bone marrow transplantations were performed as described previously (19). Briefly, recipient mice were treated with 25 mg/kg/day busulfan (Sigma-Aldrich) for 4 d, followed by injection of 200 mg/kg cyclophosphamide (Sigma-Aldrich).…”

Section: Mice Proceduresmentioning

confidence: 99%

MMP-25 Metalloprotease Regulates Innate Immune Response through NF-κB Signaling

Soria‐Valles

Gutiérrez‐Fernández

Osorio

et al. 2016

The Journal of Immunology

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Matrix metalloproteases (MMPs) regulate innate immunity acting over proinflammatory cytokines, chemokines, and other immune-related proteins. MMP-25 (membrane-type 6-MMP) is a membrane-bound enzyme predominantly expressed in leukocytes whose biological function has remained largely unknown. We have generated Mmp25-deficient mice to elucidate the in vivo function of this protease. These mutant mice are viable and fertile and do not show any spontaneous phenotype. However, Mmp25-null mice exhibit a defective innate immune response characterized by low sensitivity to bacterial LPS, hypergammaglobulinemia, and reduced secretion of proinflammatory molecules. Moreover, these immune defects can be tracked to a defective NF-κB activation observed in Mmp25-deficient leukocytes. Globally, our findings provide new mechanistic insights into innate immunity through the activity of MMP-25, suggesting that this proteinase could be a potential therapeutic target for immune-related diseases.

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Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling

Cited by 43 publications

References 50 publications

A Differentiation Transcription Factor Establishes Muscle-Specific Proteostasis in Caenorhabditis elegans

A Differentiation Transcription Factor Establishes Muscle-Specific Proteostasis in Caenorhabditis elegans

Type I insulin-like growth factor receptor signaling in hematological malignancies

MMP-25 Metalloprotease Regulates Innate Immune Response through NF-κB Signaling

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