Signaling angiogenesis via p42/p44 MAP kinase and hypoxia

Berra, Edurne; Milanini, Julie; Richard, Darren E.; Gall, Maude Le; Viñals, Francesc; Gothié, Emmanuel; Roux, Damien; Pagès, Gilles; Pouysségur, Jacques

doi:10.1016/s0006-2952(00)00423-8

Cited by 186 publications

(139 citation statements)

References 56 publications

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“…Even though the role of MAPK and PI3K pathways in the process of HIF-1␣/ VEGF activation is still controversial (Alvarez-Tejado et al, 2002;Stiehl et al, 2002), several studies evidenced that these two specific intracellular signaling pathways are actively involved in angiogenesis mediated by VEGF (Berra et al, 2000;Zhong et al, 2000;Semenza, 2002;Sang et al, 2003). Recognizing which signal transduction pathway is active in Figure 5.…”

Section: Discussionmentioning

confidence: 99%

“…Because PI3K and AKT have also been implicated in the induction of angiogenesis in response to hypoxia (Richard et al, 1999;Berra et al, 2000, Semenza, 2002bArsham et al, 2004), we evaluated AKT phosphorylation in parental cells and bcl-2 transfectants exposed to hypoxia for 24 h. Using an anti-phospho-AKT (Ser-473) antibody that recognizes the active form of AKT ( Figure 1C), an increase in AKT phosphorylation of about five-to sixfold was observed in bcl-2 transfectants compared with the parental line or control clone. Using a polyclonal antibody raised against total AKT, no modification in the level of AKT kinase expression was detected, indicating that the increase in AKT phosphorylation was not due to an increase in total AKT protein.…”

Section: Molecular Biology Of the Cell 4154mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The unique feature of HIF-1 is the regulation of HIF-1␣ expression and activity based upon the cellular O 2 concentration. HIF-1␣ expression and activity also are regulated by major signal transduction pathways, including those involving phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) (Berra et al, 2000;Semenza, 2002b). Stimulation of cells with a variety of growth factors and cytokines induces HIF-1 target gene expression under nonhypoxic conditions through activation of a variety of signal transduction pathways, including PI3K and the downstream serine-threonine protein kinase AKT (protein kinase B) and FKBP/rapamycin-associated protein (mTOR).…”

mentioning

confidence: 99%

“…Receptor tyrosine kinase activity also leads to signaling via the ERK and p38 MAP kinase pathways. PI3K and AKT also have been implicated in the induction of HIF-1 expression by hypoxia (Berra et al, 2000;Semenza, 2002b).We previously demonstrated that bcl-2 overexpression in human melanoma cells exposed to hypoxic conditions increases VEGF promoter activity and mRNA stability and enhances HIF-1 DNA binding activity (Iervolino et al, 2002 However, the steps that participate in VEGF expression mediated by HIF-1 activity in response to bcl-2 overexpression in human melanoma cells exposed to hypoxia are still unknown. We have demonstrated that the MAPK pathway is implicated in signal transduction by bcl-2 (Trisciuoglio et al, 2004).…”

mentioning

confidence: 99%

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Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

Trisciuoglio¹,

Iervolino²,

Zupi³

et al. 2005

MBoC

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We have previously demonstrated that bcl-2 overexpression in tumor cells exposed to hypoxia increases the expression of vascular endothelial growth factor (VEGF) gene through the hypoxia-inducible factor-1 (HIF-1). In this article, we demonstrate that exposure of bcl-2 overexpressing melanoma cells to hypoxia induced phosphorylation of AKT and extracellular signal-regulated kinase (ERK)1/2 proteins. On the contrary, no modulation of these pathways by bcl-2 was observed under normoxic conditions. When HIF-1␣ expression was reduced by RNA interference, AKT and ERK1/2 phosphorylation were still induced by bcl-2. Pharmacological inhibition of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways reduced the induction of VEGF and HIF-1 in response to bcl-2 overexpression in hypoxia. No differences were observed between control and bcl-2-overexpressing cells in normoxia, in terms of VEGF protein secretion and in response to PI3K and MAPK inhibitors. We also demonstrated that RNA interference-mediated down-regulation of bcl-2 expression resulted in a decrease in the ERK1/2 phosphorylation and VEGF secretion only in bcl-2-overexpressing cell exposed to hypoxia but not in control cells. In conclusion, our results indicate, for the first time, that bcl-2 synergizes with hypoxia to promote expression of angiogenesis factors in melanoma cells through both PI3K-and MAPK-dependent pathways. INTRODUCTIONAngiogenesis is a complex and multilevel process of new capillary formation on the basis of already existing blood vessels. Physiologically, it is a very strictly regulated process, which results in a balance between stimulatory (angiogenic) and inhibitory (angiostatic) factors to control the correct development of blood vessels. Angiogenesis is a rate-limiting step in tumor growth and progression, and many tumors develop a severely hypoxic microenvironment and secrete angiogenesis-stimulating factors (Folkman et al., 1971;Talks et al., 2000). Vascular endothelial growth factor (VEGF), a potent and specific mitogen for vascular endothelial cells, is a critical mediator of angiogenesis. Its expression is induced in cancer cells as a result of hypoxia and multiple genetic alterations, including p53 and PTEN loss-of-function, RAS and SRC gain-of-function, and autocrine tyrosine kinase signaling pathways (Mukhopadhyay et al., 1995;Arbiser et al., 1997;Petit et al., 1997;Akagi et al., 1998;Ellis et al., 1998;Yen et al., 2000). Based on the analysis of melanoma and breast cancer cells recently reported by our group Iervolino et al., 2002;Del Bufalo et al., 2003;Trisciuoglio et al., 2004), this list can now be extended to include the increased VEGF expression resulting from bcl-2 overexpression. Hypoxia-and growth factor-induced VEGF expression in tumor cells is regulated by the hypoxia inducible factor 1 (HIF-1) (Jiang et al., 1997;Mazure et al., 1997;Ravi et al., 2000;Zhong et al., 2000;Zundel et al., 2000;Laughner et al., 2001;Fukuda et al., 2002), a transcription factor that is compose...

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Section: Discussionmentioning

confidence: 99%

Section: Molecular Biology Of the Cell 4154mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

Trisciuoglio¹,

Iervolino²,

Zupi³

et al. 2005

MBoC

View full text Add to dashboard Cite

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Matrix-Bound VEGF Mimetic Peptides: Design and Endothelial-Cell Activation in Collagen Scaffolds

Chan

Stahl

2011

Adv. Funct. Mater.

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Long term survival and success of artificial tissue constructs depend greatly on vascularization. Endothelial cell (EC) differentiation and vasculature formation are dependent on spatio-temporal cues in the extracellular matrix that dynamically interact with cells, a process difficult to reproduce in artificial systems. Here we present a novel bifunctional peptide that mimics matrix-bound vascular endothelial growth factor (VEGF) and can be used to encode spatially controlled angiogenic signals in collagen scaffolds. The peptide is comprised of a collagen mimetic domain that was previously reported to bind to type I collagen by a unique hybridization mechanism, and a VEGF mimetic domain with pro-angiogenic activity. Circular dichroism and collagen binding studies confirm the triple helical structure and the collagen binding affinity of the collagen mimetic domain, and EC culture studies demonstrate the peptide’s ability to induce endothelial cell morphogenesis and network formation as a matrix-bound factor in 2D and 3D collagen scaffolds. We also show spatial modification of collagen substrates with this peptide that allows localized EC activation and network formation. These results demonstrate that the peptide can be used to present spatially directed angiogenic cues in collagen scaffolds, which may be useful for engineering organized microvasculature.

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Capillary Network‐Like Organization of Endothelial Cells in PEGDA Scaffolds Encoded with Angiogenic Signals via Triple Helical Hybridization

Stahl

Chan

Shen

et al. 2014

Adv Funct Materials

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Survival of tissue engineered constructs after implantation depends on proper vascularization. The differentiation of endothelial cells into mature microvasculature requires dynamic interactions between cells, scaffold, and growth factors, which are difficult to recapitulate in artificial systems. Previously, photocrosslinked poly(ethylene glycol) diacrylate (PEGDA) hydrogels displaying collagen mimetic peptides (CMPs), dubbed PEGDA‐CMP, that can be further conjugated with bioactive molecules via CMP‐CMP triple helix hybridization were reported. Here, it is shown that a bifunctional peptide featuring pro‐angiogenic domain mimicking vascular endothelial growth factor (VEGF) and a collagen mimetic domain that can fold into a triple helix conformation can hybridize with CMP side chains of the PEGDA‐CMP hydrogel, which results in presentation of insoluble VEGF‐like signals to endothelial cells. Presentation of VEGF‐like signals on the surface of micropatterned scaffolds in this way transforms cells from a quiescent state to elongated and aligned phenotype suggesting that this system could be used to engineer organized microvasculature. It is also shown that the pro‐angiogenic peptide, when applied topically in combination with modified dextran/PEGDA hydrogels, can enhance neovascularization of burn wounds in mice demonstrating the potential clinical use of CMP‐mediated matrix‐bound bioactive molecules for dermal injuries.

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Signaling angiogenesis via p42/p44 MAP kinase and hypoxia

Cited by 186 publications

References 56 publications

Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

Matrix-Bound VEGF Mimetic Peptides: Design and Endothelial-Cell Activation in Collagen Scaffolds

Capillary Network‐Like Organization of Endothelial Cells in PEGDA Scaffolds Encoded with Angiogenic Signals via Triple Helical Hybridization

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