PDGF‐BB Induces MAP Kinase Phosphorylation and VEGF Expression in Neurofibroma‐Derived Cultured Cells from Patients with Neurofibromatosis 1

Kotsuji-Maruyama, Tomoe; Imakado, Sumihisa; Kawachi, Yasuhiro; Otsuka, Fujio

doi:10.1111/j.1346-8138.2002.tb00208.x

Cited by 17 publications

(9 citation statements)

References 14 publications

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“…VEGF is expressed in nearly all cell types, but malignant tumour cells show overexpression of VEGF and this expression is closely associated with the induction and maintenance of the neovasculature in diverse tumours [Rak et al, 1995;FitzGerald et al, 2004]. The expression of VEGF may be induced by diverse agents such as IL-1b, IL-6, TGFb, PDGF-B, bFGF, and IGF-I [Stavri et al, 1995;Cohen et al, 1996;Punglia et al, 1997;Akagi et al, 1998;Berse et al, 1999;Miele et al, 2000;Jung et al, 2001;Fukuda et al, 2002;Kotsuji-Maruyama et al, 2002;Gruden et al, 2003;Menu et al, 2004]. Additionally, external stimuli, such as hypoxia, can induce VEGF expression [Kourembanas et al, 1998;Bussink et al, 2003;Choi et al, 2003].…”

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confidence: 95%

c‐Jun kinase mediates expression of VEGF induced at transcriptional level by Rac1 and Cdc42Hs but not by RhoA

Saníger¹,

Oya²,

Macías³

et al. 2006

J of Cellular Biochemistry

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Tumour angiogenesis is mediated by increased levels of vascular endothelial growth factor (VEGF). We have studied the mechanism by which endogenous activation of Rho oncoproteins regulates VEGF expression in COS-7 and NIH3T3 cells. We carried out transient and stable transfection with constitutively activated rhoA, rac1, and cdc42 mutants in COS-7 and NIH3T3 cells, respectively in the absence of external stimuli. Western blot and inmunohistochemistry assays of those cells revealed increased VEGF protein expression. Cotransfection with constitutively activated rhoA, rac1, and cdc42 mutants and a VEGF promoter-reporter construct showed an increase in VEGF promoter transcriptional activity induced by Rho oncoproteins in COS-7 and NIH3T3. c-Jun kinase had been described as a MAPK involved in Rho oncoproteins pathways. Interestingly, we found that c-Jun kinase chemical inhibition as well as transient transactivation assays using dominant negative c-Jun kinase mutant abolished the VEGF promoter transcriptional induction by Rac1 and Cdc42 but not by RhoA. These findings indicate that Rho oncoprotein endogenously activated regulates VEGF expression through a transcriptional mechanism, and that the c-Jun kinase activity is a mediator in the expression of VEGF induced by Rac1 and Cdc42 oncoproteins, but not of that induced by RhoA.

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confidence: 95%

c‐Jun kinase mediates expression of VEGF induced at transcriptional level by Rac1 and Cdc42Hs but not by RhoA

Saníger¹,

Oya²,

Macías³

et al. 2006

J of Cellular Biochemistry

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“…These include TSC, Cowden's disease, Peutz-Jeghers syndrome and Neurofibromatosis that are caused through mutations that impair the normal tumor suppressor function of TSC1 or TSC2, PTEN, LKB1, and NF1, respectively. It is known that VEGF secretion is enhanced when there is a loss of function of either one of the TSC1, TSC2 (16), PTEN (20), LKB1 (21), or NF1 (22) tumor suppressors. This suggests that the normal function of these tumor suppressors is to repress VEGF expression and this process likely involves HIF.…”

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confidence: 99%

Hypoxia-inducible Factor 1α Is Regulated by the Mammalian Target of Rapamycin (mTOR) via an mTOR Signaling Motif

Land

Tee

2007

Journal of Biological Chemistry

450

348

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Tumors that form as a result of heightened mammalian target of rapamycin (mTOR) signaling are highly vascularized. This process of angiogenesis is regulated through hypoxia-inducible factor (HIF)-mediated transcription of angiogenic factors. It is recognized that inhibition of mTOR with rapamycin can diminish the process of angiogenesis. Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1␣ and vascular endothelial growth factor (VEGF)-A secretion during hypoxia, which is reversed with rapamycin. Mutants of Rheb, which do not bind guanine nucleotide (D60K, D60V, N119I, and D122N) and are unable to activate mTOR, inhibit the activity of HIF when overexpressed. We show that regulatory associated protein of mTOR (Raptor) interacts with HIF1␣ and requires an mTOR signaling (TOS) motif located in the N terminus of HIF1␣. Furthermore, a mutant of HIF1␣ lacking this TOS motif dominantly impaired HIF activity during hypoxia and was unable to bind to the co-activator CBP/p300. Rapamycin treatments do not affect the stability of HIF1␣ and modulate HIF activity via a Von Hippel-Lindau (VHL)-independent mechanism. We demonstrate that the high levels of HIF activity in cells devoid of TSC2 can be reversed by treatments with rapamycin or the readdition of TSC2. Our work explains why human cancers with aberrant mTOR signaling are prone to angiogenesis and suggests that inhibition of mTOR with rapamycin might be a suitable therapeutic strategy.

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“…41 Human neurofibromas contain growth and angiogenesispromoting factors, including VEGF, HGF, and FGF2, and neurofibroma cells respond by proliferation to bFGF and HGF. [42][43][44][45][46][47] Our data suggest the possibility that TGF-␤, MCP-1, VEGF, and BNDF in addition to SCF may be evaluated for effects in human neurofibromas.…”

Section: Discussionmentioning

confidence: 78%

Perinatal Epidermal Growth Factor Receptor Blockade Prevents Peripheral Nerve Disruption in a Mouse Model Reminiscent of Benign World Health Organization Grade I Neurofibroma

Crimmins

Monk

et al. 2006

The American Journal of Pathology

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Benign peripheral nerve tumors called neurofibromas are a major source of morbidity for patients with neurofibromatosis type 1. Some neurofibroma Schwann cells aberrantly express the epidermal growth factor receptor (EGFR). In a mouse model in which the CNPase promoter drives expression of human EGFR in Schwann cells, nerves develop hypertrophy, mast cell accumulation, collagen deposition, disruption of axon-glial interactions, characteristics of neurofibroma and are hypoalgesic. Administration of the EGFR antagonist cetuximab (IMC-C225) for 2 weeks beginning at birth in CNPase-hEGFR mice normalized all pathologies at 3 months of age as evaluated by hotplate testing or histology and by electron microscopy. Mast cell chemoattractants brain-derived neurotrophic factor, monocyte chemoattractant protein-1, and transforming growth factor-beta1, which may account for mast cell accumulation and fibrosis, were reduced by cetuximab. Later treatment was much less effective. A birth to 2-week pulse of cetuximab blocked hEGFR phosphorylation and Schwann cell prolifera-tion in perinatal mutant nerve, so CNPase-hEGFR Schwann cell numbers correlate with the cetuximab effect. A >250-fold enlarged population of EGFR(+)/p75(+) cells was detected in newborn Nf1(+/-) mouse nerves. These results suggest the existence of an EGFR(+) cell enriched in the perinatal period capable of driving complex changes characteristic of neurofibroma formation.

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PDGF‐BB Induces MAP Kinase Phosphorylation and VEGF Expression in Neurofibroma‐Derived Cultured Cells from Patients with Neurofibromatosis 1

Cited by 17 publications

References 14 publications

c‐Jun kinase mediates expression of VEGF induced at transcriptional level by Rac1 and Cdc42Hs but not by RhoA

c‐Jun kinase mediates expression of VEGF induced at transcriptional level by Rac1 and Cdc42Hs but not by RhoA

Hypoxia-inducible Factor 1α Is Regulated by the Mammalian Target of Rapamycin (mTOR) via an mTOR Signaling Motif

Perinatal Epidermal Growth Factor Receptor Blockade Prevents Peripheral Nerve Disruption in a Mouse Model Reminiscent of Benign World Health Organization Grade I Neurofibroma

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