Hepatocyte Growth Factor Signal Coupling to Various Transcription Factors Depends on Triggering of Met Receptor and Protein Kinase Transducers in Human Hepatoma Cells HepG2

Tacchini, Lorenza; Dansi, Paola; Matteucci, Emanuela; Desiderio, Maria Alfonsina

doi:10.1006/excr.2000.4824

Cited by 33 publications

(20 citation statements)

References 48 publications

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“…The results obtained herein with a set of inhibitors have a screening value and suggest that phosphatidylinositol 3-kinase/Akt, JNK, and p38 MAPK are involved in the VEGF and HX/XO signal, whereas p42/44 is not. This pattern of activation is coincident with others already described in the literature (40). Collectively, the aforementioned results suggest that phosphatidylinositol 3-kinase/Akt, JNK, and p38 MAPK are targeted for activation in the context of VEGF-induced O 2 .…”

Section: Discussionsupporting

confidence: 89%

“…As aforementioned, the mechanisms found herein have similarities to those described for the increase of HIF-1␣ induced by other growth factors; however, our results add new information, disclosing increased HIF-1␣ gene expression upon VEGF challenge. Collectively, this group of findings provides further support to the existence of substantial differences in HIF-1 activation pathways by either growth factors or hypoxia (11,12,14,16,40).…”

Section: Discussionsupporting

confidence: 59%

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Induction of Hypoxia-inducible Factor 1α Gene Expression by Vascular Endothelial Growth Factor

Deudero

Caramelo

Castellanos

et al. 2008

Journal of Biological Chemistry

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Transcriptional regulation of vascular endothelial growth factor (VEGF) is critically dependent on hypoxia-inducible factor 1 (HIF-1). However, not only hypoxia, but selected growth factors can induce HIF-1. High levels of both VEGF and HIF-1 coexist in certain conditions, e.g. tumors. Nonetheless, the possibility that the stimulatory relationship between HIF-1 and VEGF may be bi-directional has not been addressed up to date. The present study in endothelial cells analyzed whether HIF-1 is regulated by a product of its own transcriptionally activated genes, namely, VEGF. As a main finding, VEGF-A 165 induced the increase of HIF-1␣ mRNA and HIF-1␣ protein and nuclear translocation. Autologous endothelial cell VEGF mRNA and protein were also increased upon exposure to exogenous VEGF. The signaling implication of reactive oxygen species was examined by comparison with H 2 O 2 and hypoxanthine/xanthine oxidase and by the superoxide dismutase mimetic, MnTMPyP, the Rac1-NAD(P)H oxidase complex inhibitor, apocynin, transfection of a dominant negative Rac1 mutant, and transfection of a p67phox antisense oligonucleotide. Superoxide anion, largely dependent on Rac1-NAD(P)H oxidase complex activity, was the critical signaling element. The transductional functionality of the pathway was confirmed by means of a reporter gene flanked by a transcription site-related VEGF sequence and by quantitative PCR. In summary, the present results reveal a previously undescribed action of VEGF on the expression of its own transcription factor, HIF-1, and on VEGF itself. This effect is principally mediated by superoxide anion, therefore identifying a new, potentially relevant role of reactive oxygen species in VEGF signaling.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 59%

Induction of Hypoxia-inducible Factor 1α Gene Expression by Vascular Endothelial Growth Factor

Deudero

Caramelo

Castellanos

et al. 2008

Journal of Biological Chemistry

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“…Among them, Insulin-like growth factor-1, hepatocyte growth factor, and platelet-derived growth factor have been shown to increase HIF-1␣ levels in various cell types (44,70,71). In addition, inflammatory cytokines such as tumor necrosis factor ␣, which is released from membranes by the furin substrate tumor necrosis factor ␣-converting enzyme/ ADAM17 (72), induce HIF-1 activity in normoxic conditions (73,74).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-enhanced Expression of the Proprotein Convertase Furin Is Mediated by Hypoxia-inducible Factor-1

McMahon

Grondin

McDonald

et al. 2005

Journal of Biological Chemistry

156

126

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Hypoxia is a common tumorigenesis enhancer, mostly owing to its impact on gene expression of many angiogenic and invasion-related mediators, some of which are natural substrates for the proprotein convertase furin. Analysis of furin promoters revealed the presence of putative binding sites for hypoxia-inducible factor-1 (HIF-1), a transcription complex that plays a pivotal role in cellular adaptation to hypoxia. In fact, we demonstrate herein that the levels of fur mRNA, encoding furin, are remarkably increased upon hypoxic challenge. Cotransfection of a HIF-1␣ dominant negative form in wild-type (WT) cells or transfection of a furin promoter-reporter gene in HIF-1-deficient cells indicated the requirement of HIF-1 for furin promoter activation by hypoxia. Direct HIF-1 action on the furin promoter was identified as a canonical hypoxia-responsive element site with enhancer capability. The hypoxic/ HIF-1 regulation of furin correlated with an increased proteolytic activation of the substrates membrane-type 1 matrix metalloproteinase and transforming growth factor-␤1. Our findings unveil a new facet of the physiological consequences of hypoxia/HIF-1, through enhanced furin-induced proteolytic processing/activation of proproteins known to be involved in tumorigenesis.

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“…The proto-oncogene, transcription factor c-Myc, has been demonstrated to activate this pathway. Because c-myc is a delayed-early-response gene for SF/HGF signaling in hepatocytes (26,(52)(53)(54), it seemed plausible that c-Myc could be driving cell cycle progression under contact inhibition in gliomas. Our results support this conclusion and further demonstrate that SF/HGF-mediated G 1 /S transition occurs in these cells independent of p27, Cdk2, and E2F1.…”

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confidence: 99%

Scatter Factor/Hepatocyte Growth Factor Stimulation of Glioblastoma Cell Cycle Progression through G₁ Is c-Myc Dependent and Independent of p27 Suppression, Cdk2 Activation, or E2F1-Dependent Transcription

Walter

Hossain

Luddy

et al. 2002

Molecular and Cellular Biology

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Scatter factor/hepatocyte growth factor (SF/HGF) expression has been linked to malignant progression in glial neoplasms. Using two glioma cell lines, U373MG and SNB-19, we have demonstrated that SF/HGF stimulation allows cells to escape G1/G0 arrest induced by contact inhibition or serum withdrawal. SF/HGF induced effects on two mechanisms of cell cycle regulation: suppression of the cyclin-dependent kinase inhibitor p27 and induction of the transcription factor c-Myc. Regulation of p27 by SF/HGF was posttranslational and is associated with p27 nuclear export. Transient transfections of U373MG and SNB-19 with wild-type p27 and a degradation-resistant p27T187A mutant were insufficient to induce cell cycle arrest, and SF/HGF downregulation of p27 was not necessary for cell cycle reentry. Analysis of Cdk2 kinase activity and p27 binding to cyclin E complexes in the presence of exogenous wild-type p27 or p27T187A demonstrated that Cdk2 activity was not necessary for SF/HGF-mediated G1/S transition. Similarly, overexpression of dominant-negative forms of Cdk2 did not block SF/HGF-triggered cell cycle progression. In contrast, SF/HGF transcriptionally upregulated c-Myc, and overexpression of c-Myc was able to prevent G1/G0 arrest in the absence of SF/HGF. Transient overexpression of MadMyc, a dominant-negative chimera for c-Myc, caused G1/G0 arrest in logarithmically growing cells and blocked SF/HGF-mediated G1/S transition. c-Myc did not exert its effects through p27 downregulation in these cell lines. SF/HGF induced E2F1-dependent transcription, the inhibition of which did not block SF/HGF-induced cell cycle progression. We conclude that SF/HGF prevents G1/G0 arrest in glioma cell lines by a c-myc-dependent mechanism that is independent of p27, Cdk2, or E2F1

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Hepatocyte Growth Factor Signal Coupling to Various Transcription Factors Depends on Triggering of Met Receptor and Protein Kinase Transducers in Human Hepatoma Cells HepG2

Cited by 33 publications

References 48 publications

Induction of Hypoxia-inducible Factor 1α Gene Expression by Vascular Endothelial Growth Factor

Induction of Hypoxia-inducible Factor 1α Gene Expression by Vascular Endothelial Growth Factor

Hypoxia-enhanced Expression of the Proprotein Convertase Furin Is Mediated by Hypoxia-inducible Factor-1

Scatter Factor/Hepatocyte Growth Factor Stimulation of Glioblastoma Cell Cycle Progression through G₁ Is c-Myc Dependent and Independent of p27 Suppression, Cdk2 Activation, or E2F1-Dependent Transcription

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Hepatocyte Growth Factor Signal Coupling to Various Transcription Factors Depends on Triggering of Met Receptor and Protein Kinase Transducers in Human Hepatoma Cells HepG2

Cited by 33 publications

References 48 publications

Induction of Hypoxia-inducible Factor 1α Gene Expression by Vascular Endothelial Growth Factor

Induction of Hypoxia-inducible Factor 1α Gene Expression by Vascular Endothelial Growth Factor

Hypoxia-enhanced Expression of the Proprotein Convertase Furin Is Mediated by Hypoxia-inducible Factor-1

Scatter Factor/Hepatocyte Growth Factor Stimulation of Glioblastoma Cell Cycle Progression through G1 Is c-Myc Dependent and Independent of p27 Suppression, Cdk2 Activation, or E2F1-Dependent Transcription

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Scatter Factor/Hepatocyte Growth Factor Stimulation of Glioblastoma Cell Cycle Progression through G₁ Is c-Myc Dependent and Independent of p27 Suppression, Cdk2 Activation, or E2F1-Dependent Transcription