SU1498, an Inhibitor of Vascular Endothelial Growth Factor Receptor 2, Causes Accumulation of Phosphorylated ERK Kinases and Inhibits Their Activity in Vivo and in Vitro

Boguslawski, George; McGlynn, Patrick; Harvey, Kevin; Kovala, A. Thomas

doi:10.1074/jbc.m308625200

Cited by 38 publications

(30 citation statements)

References 63 publications

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“…4C). Although SU1498 is reported to inhibit not only Flk1 downstream kinase activation but also other receptor tyrosine kinases (PDGF, EGF, or FGF), SU1498 still strongly inhibits on VEGF-A signaling cascade (Boguslawski et al, 2004). This later result suggests that neural precursor cells in neurosphere culture release endogenous VEGF-A and that this endogenous VEGF-A facilitates neurosphere formation.…”

Section: Addition Of Vegf-mentioning

confidence: 53%

Vascular Endothelial Growth Factor Directly Inhibits Primitive Neural Stem Cell Survival But Promotes Definitive Neural Stem Cell Survival

Wada

Haigh

Ema

et al. 2006

Journal of Neuroscience

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Section: Addition Of Vegf-mentioning

confidence: 53%

Vascular Endothelial Growth Factor Directly Inhibits Primitive Neural Stem Cell Survival But Promotes Definitive Neural Stem Cell Survival

Wada

Haigh

Ema

et al. 2006

Journal of Neuroscience

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“…However, it has been reported that SU1498 stimulates accumulation of phosphorylated ERKs in HUVECs and in human aortic endothelial cells, but the inhibitor blocked the kinase activity of phospho-ERK both in a direct assay and in immunoprecipitates. These findings reveal a novel and unique way in which MAPK signaling pathway may be blocked by SU1498 in human endothelial cells [35]. The effects of genistein on neovascularization, VEGF, and hypoxia inducible factor 1a (HIF-1a) protein expression in a mouse model of oxygen-induced retinopathy were studied.…”

Section: Discussionmentioning

confidence: 99%

Hyperbaric oxygen induces VEGF expression through ERK, JNK and c-Jun/AP-1 activation in human umbilical vein endothelial cells

Lee

Chen

Tsai³

et al. 2005

J Biomed Sci

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SummaryHyperbaric oxygen (HBO) is increasingly used in a number of areas of medical practice, such as selected problem infections and wounds. The beneficial effects of HBO in treating ischemia-related wounds may be mediated by stimulating angiogenesis. We sought to investigate VEGF, the main angiogenic regulator, regulated by HBO in human umbilical vein endothelial cells (HUVECs). In this study, we found that VEGF was up regulated both at mRNA and protein levels in HUVECs treated with HBO dose-and timedependently. Since there are several AP-1 sites in the VEGF promoter, and the c-Jun/AP-1 is activated through stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and extracellular signal regulated kinase (ERK), we further examined the c-Jun, JNK and ERK that might be involved in the VEGF induced by HBO. The VEGF mRNA induced by HBO was blocked by both PD98059 and SP600125, the ERK and JNK inhibitors respectively. HBO induced phospho-ERK and phospho-JNK expressions within 15 min. We further demonstrated that c-Jun phosphorylation was induced within 60 min of HBO treatment. HBO also induced the nuclear AP-1 binding ability within 30-60 min, but the AP-1 induction was blocked by treatment with either the ERK or JNK inhibitor. To verify that the VEGF expression induced by HBO is through the AP-1 trans-activation and VEGF promoter, both the VEGF promoter and AP-1 driving luciferase activity were found increased by the cells treated with HBO. The c-Jun mRNA, which is also driven by AP-1, was also induced by HBO, and the induction of c-Jun was blocked by ERK and JNK inhibitors. We suggest that VEGF induced by HBO is through c-Jun/AP-1 activation, and through simultaneous activation of ERK and JNK pathways.

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“…7C, bars 1 and 3). SU1498 is known to block extracellular signal-regulated kinase (ERK) signaling, which might contribute to its inhibitory effect on control cells (4). However, the addition of SU1498 to PRH KD cells abolishes the growth-stimulatory effect of PRH KD and reduces the number of KD cells to around the same level seen after treatment of the control cells (Fig.…”

Section: Prh Repressesmentioning

confidence: 99%

PRH/Hhex Controls Cell Survival through Coordinate Transcriptional Regulation of Vascular Endothelial Growth Factor Signaling

Noy

Williams

Sawasdichai

et al. 2010

Molecular and Cellular Biology

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The proline-rich homeodomain protein (PRH) plays multiple roles in the control of gene expression during embryonic development and in the adult. Vascular endothelial growth factor (VEGF) is a mitogen that stimulates cell proliferation and survival via cell surface receptors including VEGFR-1 and VEGFR-2. VEGF signaling is of critical importance in angiogenesis and hematopoiesis and is elevated in many tumors. Here we show that PRH binds directly to the promoter regions of the Vegf, Vegfr-1, and Vegfr-2 genes and that in each case PRH represses transcription. We demonstrate that overexpression or knockdown of PRH directly impinges on the survival of both leukemic and tumor cells and that the modulation of VEGF and VEGF receptor signaling by PRH mediates these effects. Our findings demonstrate that PRH is a key regulator of the VEGF signaling pathway and describe a mechanism whereby PRH plays an important role in tumorigenesis and leukemogenesis.

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SU1498, an Inhibitor of Vascular Endothelial Growth Factor Receptor 2, Causes Accumulation of Phosphorylated ERK Kinases and Inhibits Their Activity in Vivo and in Vitro

Cited by 38 publications

References 63 publications

Vascular Endothelial Growth Factor Directly Inhibits Primitive Neural Stem Cell Survival But Promotes Definitive Neural Stem Cell Survival

Vascular Endothelial Growth Factor Directly Inhibits Primitive Neural Stem Cell Survival But Promotes Definitive Neural Stem Cell Survival

Hyperbaric oxygen induces VEGF expression through ERK, JNK and c-Jun/AP-1 activation in human umbilical vein endothelial cells

PRH/Hhex Controls Cell Survival through Coordinate Transcriptional Regulation of Vascular Endothelial Growth Factor Signaling

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