Transforming Growth Factor β2 inhibition of Hepatocyte Growth Factor-induced endothelial proliferation and migration

Manganini, Massimiliano; Maier, Jeanette A.M.

doi:10.1038/sj.onc.1203225

Cited by 25 publications

(17 citation statements)

References 35 publications

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“…49 Inhibition of retinal angiogenesis by interruption of TSP-1's activation of TGF-␤ 50 suggests that bioactivation of TGF-␤ may be one mechanism responsible for TSP-1-induced antiangiogenesis. An antiangiogenic function in vivo was suggested for TGF-␤2 based on its inhibitory effect on hepatocyte growth factor-mediated angiogenesis, 51 whereas experimental evidence suggests that TGF-␤1 has proangiogenic 52 and proapoptotic effects. 53,54 Since TGF-␤2 is only minimally expressed in vascular endothelium under normoxic conditions, 55,56 the degree to which hypoxic induction of TGF-␤2, as distinct from TGF-␤1 or TGF-␤3, is associated with regulation of apoptosis and angiogenesis in endothelium has remained unclear.…”

Section: Discussionmentioning

confidence: 99%

Cellular response to hypoxia involves signaling via Smad proteins

Zhang

Akman

Smith

et al. 2003

Blood

134

111

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IntroductionThe transforming growth factor-␤ (TGF-␤) family of growth factors mediates vascular development and regulates endothelial responses to mechanical, inflammatory, and hypoxic stress. [1][2][3][4][5][6][7][8][9][10] The important role of TGF-␤ in vascular physiology is indicated by defective vasculogenesis and striking vascular inflammation leading to death in mice null for TGF-␤s, their receptors, or their downstream substrates, the Smad proteins. 3,7,11,12 We recently have shown that exposure of human umbilical vein endothelial cells (HUVECs) to hypoxia (1% O 2 ) selectively up-regulates transcription and expression of TGF-␤2 by as much as 20-fold and induces Smad2, Smad3, and Smad4 to associate with DNA. 9 In vascular endothelium, TGF-␤2, similar to TGF-␤1 and TGF-␤3, is produced in a latent form in which the bioactive, 25-kDa TGF-␤ dimer (mature TGF-␤) is noncovalently bound to its propeptide (also known as latency-associated peptide [LAP]) and is unavailable for binding to TGF-␤ membrane receptors. 1 An important physiologic regulator of TGF-␤ bioactivation is thrombospondin-1 (TSP-1), an extracellular matrix protein that is a member of the TSP family of glycoproteins. [13][14][15] TSP-1, a trimer of disulfide-linked 180-kDa subunits, is secreted from platelet ␣-granules, endothelial cells, and vascular smooth muscle cells, and is deposited in extracellular matrix. 16 Binding of TSP-1 to LAP occurs via amino acid sequence K 412 RFK 415 of TSP-1 and amino acid sequence L 54 SKL 57 of LAP, 15,17 and potentially induces a conformational change in LAP that allows interaction of the 25-kDa mature TGF-␤ peptide with its specific membrane receptors. TSP-1 can activate LAPs associated with both latent TGF-␤1 and -␤2, 15 and similarities reported between TGF-␤1-null and TSP-1-null animals 17,18 suggest that TSP-1-mediated TGF-␤ bioactivation is physiologically significant.Mature TGF-␤ can bind to its type I, type II, and type III cell membrane receptors, the first 2 of which are serine/threonine kinases. 19 Once activated by TGF-␤, the type II receptor transphosphorylates the type I receptor, which then phosphorylates Smad2 or Smad3 (receptor-activated Smads [R-Smads]), which in turn heteromerize with Smad4 (Co-Smad) to translocate to the nucleus. Smad complexes accumulate in the nucleus, where they regulate gene transcription by recruiting transcriptional coactivators or inhibitors to DNA. 19 This cross-talk created by the interplay between Smads and other signaling pathways is largely responsible for the diverse and context-specific effects of the TGF-␤ family of proteins.The Smad signaling pathway was recently shown to interact with the transacting protein complex hypoxia-inducible factor-1 (HIF-1), which is a well-characterized transcription factor complex that regulates hypoxia-driven gene expression. 20,21 HIF-1 binds DNA as a heterodimer of 2 basic helix-loop-helix proteins, HIF-1␣ and the aryl hydrocarbon receptor nuclear translocator (ARNT, or HIF-1␤). 22,23 Under normoxic conditions, HIF-1␣ is ra...

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Section: Discussionmentioning

confidence: 99%

Cellular response to hypoxia involves signaling via Smad proteins

Zhang

Akman

Smith

et al. 2003

Blood

134

111

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“…Alternatively, suramin may induce Src activation by blocking TGF-␤ binding to its receptor. In this context, it has been reported that TGF-␤ treatment decreases Src activity and cell growth in the prostate carcinoma cell line PC3 and hepatoma cell line HepG2 (Atfi et al, 1994;Fukuda et al, 1998) and prevents hepatocyte growth factorinduced tyrosine phosphorylation of Src and migration in endothelial cells (Manganini and Maier, 2000).…”

Section: Discussionmentioning

confidence: 99%

Suramin Promotes Proliferation and Scattering of Renal Epithelial Cells

Zhuang

Schnellmann

2005

J Pharmacol Exp Ther

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Primary cultures of renal proximal tubules are known to recapitulate several early events in the process of renal regeneration following injury. In this study, we show that suramin, a polysulfonated naphthylurea, stimulates outgrowth, scattering, and proliferation of primary cultures of renal proximal tubule cells (RPTC). These responses were comparable to those produced by epidermal growth factor (EGF). However, AG-1478 [4-(3Ј-chloroanilino)-6,7-dimethoxy-quinazoline], a specific inhibitor of the EGF receptor, blocked EGF but not suramin-induced RPTC outgrowth, scattering, and proliferation. Suramin stimulated phosphorylation of Akt, a downstream kinase of phosphoinositide 3-kinase (PI3K), extracellular signaling-regulated kinase 1/2 (ERK1/2), and Src, but not the EGF receptor. Blockade of Src, but not the EGF receptor, inhibited Akt and ERK1/2 phosphorylation. Furthermore, inactivation of PI3K with LY294002 [2-(4morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] blocked suramin-induced RPTC outgrowth, scattering, and proliferation, whereas blockade of ERK1/2 had no effect. These data identify novel effects of suramin in RPTC outgrowth, scattering, and proliferation. Furthermore, suramininduced outgrowth, scattering, and proliferation of RPTC are through Src-mediated activation of the PI3K pathway but not ERK1/2 or the EGF receptor.

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“…A recent study has shown that TGF-␤2 gene is specifically induced after infection of HUVECs with an adenovirus gene transfer vector that confers prolonged survival to endothelial cells even in the absence of serum. 77 Furthermore, exposure of endothelial cells to TGF-␤2 was shown to counteract the angiogenic effects of hepatocyte growth factor via inhibition of its signaling, 78 and antibody to TGF-␤2 was shown to stimulate DNA synthesis in pericytes. 79 Based on these and previous findings regarding the antiinflammatory role of the TGF-␤ family of cytokines, 75,[80][81][82] we hypothesize that TGF-␤2 induces an antiproliferative, antiapoptotic, and antiangiogenic signal to mitigate the inflammatory signals induced by hypoxia and augments an adaptive response in the endothelium.…”

Section: Discussionmentioning

confidence: 99%

Response to hypoxia involves transforming growth factor-β2 and Smad proteins in human endothelial cells

Akman

Zhang

Siddiqui

et al. 2001

Blood

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Oxygen deprivation (hypoxia) is a consistent component of ischemia that induces an inflammatory and prothrombotic response in the endothelium. In this report, it is demonstrated that exposure of endothelial cells to hypoxia (1% O 2 ) increases messenger RNA and protein levels of transforming growth factor-␤2 (TGF-␤2), a cytokine with potent regulatory effects on vascular inflammatory responses. Messenger RNA levels of the TGF-␤2 type II membrane receptor, which is a serine threonine kinase, also increased. The stimulatory effect of hypoxia was found to occur at the level of transcription of the TGF-␤2 gene and involves Smad proteins, a class of intracellular signaling proteins that mediates the downstream effects of TGF-␤ receptors. Transient transfection studies showed that the region spanning ؊77 and ؊40 base pairs within the TGF-␤2 promoter (harboring a Smad-binding "CAGA box") is activated in hypoxic cells compared with nonhypoxic controls (P < .01). Hypoxia also stimulated transcription from another promoter, 3TP-Lux, a reporter construct responsive to Smads and TGF-␤. In addition, specific binding to a Smad-binding oligonucleotide was observed with nuclear extracts from hypoxic endothelial cells but not from nonhypoxic cells. It is concluded that Smad proteins, which can regulate endothelial responses to mechanical and inflammatory stress, also may play an important role in vascular responses to hypoxia and ischemia. IntroductionOne of the earliest responses of endothelium to hypoxia is inflammation, and the balance between positive and negative regulators of this inflammatory response is a determinant of endothelial adaptation to hypoxia. Proinflammatory endothelial responses induced by hypoxia involve production of cytokines, chemokines, 1-3 tissue factor, 4 and plasminogen activator inhibitor-1 (PAI-1). 5 Recent studies indicate that activation of the transcription factor early growth response-1 (Egr-1) by hypoxia is responsible for the procoagulant profile and vascular remodeling that ultimately result in the tissue damage associated with ischemia. 4 Adaptive responses to hypoxia are also regulated at a transcriptional level, which is best exemplified by activation of the transacting protein hypoxia-inducible factor-1 (HIF-1), which stimulates differential expression of specific genes and results in increases in glucose uptake, glycolytic enzyme production, and angiogenesis. 6,7 The transforming growth factor-␤ (TGF-␤) family of growth factors has an especially critical role in modulation of vascular inflammatory responses and remodeling, [8][9][10] and up-regulation of TGF-␤ production is an invariant response to vascular injury, indicating that regulation of gene expression of the TGF-␤ proteins by quiescent and injured endothelium is likely to be a critical factor affecting the course of vascular inflammation. This hypothesis is supported by demonstration of defective vasculogenesis and increased and ultimately lethal vascular inflammation in mice null for TGF-␤s, 11,12 their membrane receptors, 13...

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Transforming Growth Factor β2 inhibition of Hepatocyte Growth Factor-induced endothelial proliferation and migration

Cited by 25 publications

References 35 publications

Cellular response to hypoxia involves signaling via Smad proteins

Cellular response to hypoxia involves signaling via Smad proteins

Suramin Promotes Proliferation and Scattering of Renal Epithelial Cells

Response to hypoxia involves transforming growth factor-β2 and Smad proteins in human endothelial cells

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