IFNs are effective in inhibiting angiogenesis in preclinical models and in treating several angio-proliferative disorders. However, the detailed mechanisms of IFNα-mediated anti-angiogenesis are not completely understood. Stat1/2/3 and PML are IFNα downstream effectors and are pivotal regulators of angiogenesis. Here, we investigated PML′s role in the regulation of Stat1/2/3 activity. In Pml knockout (KO) mice, ablation of Pml largely reduces IFNα angiostatic ability in Matrixgel plug assays. This suggested an essential role for PML in IFNα′s anti-angiogenic function. We also demonstrated that PML shared a large cohort of regulatory genes with Stat1 and Stat3, indicating an important role of PML in regulating Stat1 and Stat3 activity. Using molecular tools and primary ECs, we demonstrated that PML positively regulates Stat1 and Stat2 isgylation, a ubiquitination-like protein modification. Accordingly, manipulation of the isgylation system by knocking down USP18 altered IFNα-PML axis-mediated inhibition of EC migration and network formation. Furthermore, PML promotes turnover of nuclear Stat3 and knockdown of PML mitigates the effect of LLL12, a selective Stat3 inhibitor, on IFNα-mediated anti-angiogenic activity. Taken together, we elucidated an unappreciated mechanism in which PML, an IFNα-inducible effector, possess potent angiostatic activity, doing so in part, by forming a positive feedforward loop with Stat1/2 and a negative feedback loop with Stat3. The interplay between PML, Stat1/Stat2 and Stat3 contributes to IFNα-mediated inhibition of angiogenesis and disruption of this network results in aberrant IFNα signaling and altered angiostatic activity.
from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2pOqUjb
via IFTTT
Εγγραφή σε:
Σχόλια ανάρτησης (Atom)
Δημοφιλείς αναρτήσεις
-
Publication date: Available online 4 January 2018 Source: European Journal of Radiology Author(s): Peiyao Zhang, Jing Wang, Qin Xu, Zhen...
-
BACKGROUND AND PURPOSE: Lesion load is a common biomarker in multiple sclerosis, yet it has historically shown modest association with cl...
-
Does CBD Oil Lower Blood Pressure? This article was originally published at SundayScaries." Madeline Taylor POSTED ON January 13, 20...
-
Despite widespread journal endorsement of reporting guidelines, the poor reproducibility of preclinical research is increasingly under debat...
-
The benefit of the breastfeeding has been well-established. In comparison to partial breast feeding, exclusive breastfeeding has even more b...
-
A report of the Cold Spring Harbor Laboratory/Wellcome Trust Meeting on Engineering Principles in Biology, Cambridge, UK, 14-16 October 2009...
-
Abstract We report here a microscopic tight-binding theoretical study of the dynamic dielectric response of graphene-on-polarizable substr...
-
Volumetry measurement of lung nodules is gaining clinical acceptance but still... Read more on AuntMinnieEurope.com Related Reading: Ul...
-
Background Hyperthyroidism is associated with increased thrombotic risk. As contact system activation through formation of neutrophil extrac...
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου