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Open AccessArticle

The PERK Branch of the Unfolded Protein Response Promotes DLL4 Expression by Activating an Alternative Translation Mechanism

1
Inserm UMR1037, CRCT (Cancer Research Center of Toulouse), CNRS ERL5294, Université Toulouse III Paul-Sabatier, F-31037 Toulouse, France
2
Vectorology Plateform, Technological pole CRCT, F-31037 Toulouse, France
3
Inserm UMR1048, I2MC (Institut des Maladies Métaboliques et Cardiovasculaires), Toulouse, France
*
Author to whom correspondence should be addressed.
These two authors contributed equally to this work.
Cancers 2019, 11(2), 142; https://doi.org/10.3390/cancers11020142
Received: 3 December 2018 / Revised: 15 January 2019 / Accepted: 22 January 2019 / Published: 25 January 2019
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
Delta-like 4 (DLL4) is a pivotal endothelium specific Notch ligand that has been shown to function as a regulating factor during physiological and pathological angiogenesis. DLL4 functions as a negative regulator of angiogenic branching and sprouting. Interestingly, Dll4 is with Vegf-a one of the few examples of haplo-insufficiency, resulting in obvious vascular abnormalities and in embryonic lethality. These striking phenotypes are a proof of concept of the crucial role played by the bioavailability of VEGF and DLL4 during vessel patterning and that there must be a very fine-tuning of DLL4 expression level. However, to date the expression regulation of this factor was poorly studied. In this study, we showed that the DLL4 5′-UTR harbors an Internal Ribosomal Entry Site (IRES) that, in contrast to cap-dependent translation, was efficiently utilized in cells subjected to several stresses including hypoxia and endoplasmic reticulum stress (ER stress). We identified PERK, a kinase activated by ER stress, as the driver of DLL4 IRES-mediated translation, and hnRNP-A1 as an IRES-Trans-Acting Factor (ITAF) participating in the IRES-dependent translation of DLL4 during endoplasmic reticulum stress. The presence of a stress responsive internal ribosome entry site in the DLL4 msRNA suggests that the process of alternative translation initiation, by controlling the expression of this factor, could have a crucial role in the control of endothelial tip cell function. View Full-Text
Keywords: DLL4 (delta like ligand 4); angiogenesis; IRES (internal ribosome entry site); hypoxia; endoplasmic reticulum stress; UPR (unfolded protein response); PERK (PKR-Like endoplasmic reticulum kinase) DLL4 (delta like ligand 4); angiogenesis; IRES (internal ribosome entry site); hypoxia; endoplasmic reticulum stress; UPR (unfolded protein response); PERK (PKR-Like endoplasmic reticulum kinase)
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Jaud, M.; Philippe, C.; Van Den Berghe, L.; Ségura, C.; Mazzolini, L.; Pyronnet, S.; Laurell, H.; Touriol, C. The PERK Branch of the Unfolded Protein Response Promotes DLL4 Expression by Activating an Alternative Translation Mechanism. Cancers 2019, 11, 142.

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