TY - JOUR A1 - Briest, Franziska A1 - Grass, Irina A1 - Sedding, Dagmar A1 - Moebs, Markus A1 - Christen, Friederike A1 - Benecke, Joana A1 - Fuchs, Karolin A1 - Mende, Stefanie A1 - Kaemmerer, Daniel A1 - Sänger, Jörg A1 - Kunze, Almut A1 - Geisler, Christina A1 - Freitag, Helma A1 - Lewens, Florentine A1 - Worpenberg, Lina A1 - Iwaszkiewicz, Sara A1 - Siegmund, Britta A1 - Walther, Wolfgang A1 - Hummel, Michael A1 - Grabowski, Patricia T1 - Mechanisms of Targeting the MDM2-p53-FOXM1 Axis in Well-Differentiated Intestinal Neuroendocrine Tumors JF - Neuroendocrinology : international journal for basic and clinical studies on neuroendocrine relationships N2 - Background/Aims: The tumor suppressor p53 is rarely mutated in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) but they frequently show a strong expression of negative regulators of p53, rendering these tumors excellent targets for a p53 recovery therapy. Therefore, we analyzed the mechanisms of a p53 recovery therapy on intestinal neuroendocrine tumors in vitro and in vivo. Methods: By Western blot and immunohistochemistry, we found that in GEP-NEN biopsy material overexpression of MDM2 was present in intestinal NEN. Therefore, we analyzed the effect of a small-molecule inhibitor, nutlin-3a, in p53 wild-type and mutant GEP-NEN cell lines by proliferation assay, flow cytometry, immunofluorescence, Western blot, and by multiplex gene expression analysis. Finally, we analyzed the antitumor effect of nutlin-3a in a xenograft mouse model in vivo. During the study, the tumor volume was determined. Results: The midgut wild-type cell line KRJ-I responded to the treatment with cell cycle arrest and apoptosis. By gene expression analysis, we could demonstrate that nutlins reactivated an antiproliferative p53 response. KRJ-I-derived xenograft tumors showed a significantly decreased tumor growth upon treatment with nutlin-3a in vivo. Furthermore, our data suggest that MDM2 also influences the expression of the oncogene FOXM1 in a p53-independent manner. Subsequently, a combined treatment of nutlin-3a and cisplatin (as chemoresistance model) resulted in synergistically enhanced antiproliferative effects. Conclusion: In summary, MDM2 overexpression is a frequent event in p53 wild-type intestinal neuroendocrine neoplasms and therefore recovery of a p53 response might be a novel personalized treatment approach in these tumors. (c) 2017 S. Karger AG, Basel KW - Neuroendocrine tumors KW - Signaling KW - MDM2 KW - p53 KW - FOXM1 KW - Targeted therapy Y1 - 2017 U6 - https://doi.org/10.1159/000481506 SN - 0028-3835 SN - 1423-0194 VL - 107 IS - 1 SP - 1 EP - 23 PB - Karger CY - Basel ER - TY - JOUR A1 - de Vinuesa, Amaya Garcia A1 - Abdelilah-Seyfried, Salim A1 - Knaus, Petra A1 - Zwijsen, An A1 - Bailly, Sabine T1 - BMP signaling in vascular biology and dysfunction JF - New journal of physics : the open-access journal for physics N2 - The vascular system is critical for developmental growth, tissue homeostasis and repair but also for tumor development. Bone morphogenetic protein (BMP) signaling has recently emerged as a fundamental pathway of the endothelium by regulating cardiovascular and lymphatic development and by being causative for several vascular dysfunctions. Two vascular disorders have been directly linked to impaired BMP signaling: pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia. Endothelial BMP signaling critically depends on the cellular context, which includes among others vascular heterogeneity, exposure to flow, and the intertwining with other signaling cascades (Notch, WNT, Hippo and hypoxia). The purpose of this review is to highlight the most recent findings illustrating the clear need for reconsidering the role of BMPs in vascular biology. (C) 2015 Elsevier Ltd. All rights reserved. KW - Bone morphogenetic proteins (BMP) KW - Signaling KW - Vasculature KW - Development KW - Disease Y1 - 2016 U6 - https://doi.org/10.1016/j.cytogfr.2015.12.005 SN - 1359-6101 SN - 1879-0305 VL - 27 SP - 65 EP - 79 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Müller-Röber, Bernd A1 - Balazadeh, Salma T1 - Auxin and its role in plant senescence JF - Journal of plant growth regulation N2 - Leaf senescence represents a key developmental process through which resources trapped in the photosynthetic organ are degraded in an organized manner and transported away to sustain the growth of other organs including newly forming leaves, roots, seeds, and fruits. The optimal timing of the initiation and progression of senescence are thus prerequisites for controlled plant growth, biomass accumulation, and evolutionary success through seed dispersal. Recent research has uncovered a multitude of regulatory factors including transcription factors, micro-RNAs, protein kinases, and others that constitute the molecular networks that regulate senescence in plants. The timing of senescence is affected by environmental conditions and abiotic or biotic stresses typically trigger a faster senescence. Various phytohormones, including for example ethylene, abscisic acid, and salicylic acid, promote senescence, whereas cytokinins delay it. Recently, several reports have indicated an involvement of auxin in the control of senescence, however, its mode of action and point of interference with senescence control mechanisms remain vaguely defined at present and contrasting observations regarding the effect of auxin on senescence have so far hindered the establishment of a coherent model. Here, we summarize recent studies on auxin-related genes that affect senescence in plants and highlight how these findings might be integrated into current molecular-regulatory models of senescence. KW - ARF KW - Auxin KW - Chloroplast KW - Development KW - Leaf KW - SAUR KW - Senescence KW - Signaling KW - Transcription factor KW - YUCCA Y1 - 2014 U6 - https://doi.org/10.1007/s00344-013-9398-5 SN - 0721-7595 SN - 1435-8107 VL - 33 IS - 1 SP - 21 EP - 33 PB - Springer CY - New York ER -