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81.
Vascular endothelial growth factor (VEGF), a critical regulator in angiogenesis, exerts its angiogenic effect via binding to its receptor, VEGF receptor-2 tyrosine kinase (VEGFR2) or kinase insert domain-containing receptor (Kdr), on the surface of endothelial cells. Kdr-mediated signaling plays an important role in the proliferation, migration, differentiation, and survival of endothelial cells. Therefore, the inhibition of this signaling pathway represents a promising therapeutic approach for the discovery of novel anticancer agents by destabilizing the progression of solid tumors via abrogating tumor-induced angiogenesis. To explore Kdr as an anticancer target and further characterize the enzyme, we purified a cytoplasmic domain of human Kdr (Kdr-CD) and characterized its autophosphorylation activity. We also designed and synthesized peptides containing amino acid sequences corresponding to the autophosphorylation sites of Kdr and developed a simple, robust, high-throughput assay for measuring the phosphate transfer activity of the enzyme. This assay was validated by the experiments showing that the phosphate transfer activity of the purified Kdr-CD required Mg2+ or Mn2+ and preactivation by adenosine 5'-triphosphate (ATP) and was inhibited by known Kdr inhibitors. Using this assay, we examined effects of Mg2+ and Mn2+ on the enzyme activity; optimized the concentrations of Kdr-CD, peptide and ATP substrates, and metal ions in the assay; and determined the kinetic properties of the enzyme for the peptide and ATP as well as IC50 values of two known Kdr inhibitors. Thus, the results of these studies have validated the utilities of this assay for biochemical characterizations of the enzyme and its inhibitors. This approach of designing peptides corresponding to the autophosphorylation sites of Kdr as substrates for the enzyme has general practical implications to other kinases. 相似文献
82.
Oka N Soeda A Inagaki A Onodera M Maruyama H Hara A Kunisada T Mori H Iwama T 《Biochemical and biophysical research communications》2007,360(3):553-559
There is increasing evidence for the presence of cancer stem cells (CSCs) in malignant brain tumors, and these CSCs may play a pivotal role in tumor initiation, growth, and recurrence. Vascular endothelial growth factor (VEGF) promotes the proliferation of vascular endothelial cells (VECs) and the neurogenesis of neural stem cells. Using CSCs derived from human glioblastomas and a retrovirus expressing VEGF, we examined the effects of VEGF on the properties of CSCs in vitro and in vivo. Although VEGF did not affect the property of CSCs in vitro, the injection of mouse brains with VEGF-expressing CSCs led to the massive expansion of vascular-rich GBM, tumor-associated hemorrhage, and high morbidity, suggesting that VEGF promoted tumorigenesis via angiogenesis. These results revealed that VEGF induced the proliferation of VEC in the vascular-rich tumor environment, the so-called stem cell niche. 相似文献
83.
84.
Thapa N Lee BH Kim IS 《The international journal of biochemistry & cell biology》2007,39(12):2183-2194
TGFBIp/βig-h3 protein is an extracellular matrix molecule initially cloned from human adenocarcinoma cells treated with TGF-β. Its precise function remains obscure but a number of studies have demonstrated it to be an intriguingly versatile molecule role in a wide range of physiological and pathological conditions. To date, the most extensively studied and reported action of TGFBIp/βig-h3 protein is in corneal dystrophy and several excellent reviews are available on this. Work from various laboratories on this molecule has compiled a tremendous amount of information over the past decade and a half. Here we review the current understanding on TGFBIp/βig-h3 protein and its functions in morphogenesis, extracellular matrix interactions, adhesion/migration, corneal dystrophy, tumorigenesis, angiogenesis, nephropathies, osteogenesis, wound healing and inflammation. 相似文献
85.
Karagiannis ED Popel AS 《The international journal of biochemistry & cell biology》2007,39(12):2314-2323
Angiogenesis, or neovascularization, is tightly orchestrated by endogenous regulators that promote or inhibit the process. The fine-tuning of these pro- and anti-angiogenic elements (the angiogenic balance) helps establish the homeostasis in tissues, and any aberration leads to pathologic conditions. The type I thrombospondin repeats are a family of protein structural elements involved in the control of angiogenesis, and some proteins containing these repeats have been identified as negative regulators of angiogenesis. Here we identify a set of 11 novel, anti-angiogenic 18–20-amino acid peptides that are derived from proteins that belong to the CCN protein family and contain type I thrombospondin motifs. We have named these peptides spondinstatin-1, cyrostatin, connectostatin, nephroblastostatin, wispostatin-2, wispostatin-3, netrinstatin-5C, netrinstatin-5D, adamtsostatin-like-4, fibulostatin-6.1, and complestatin-C6 to reflect their origin. We have shown that these peptides inhibit proliferation and migration of human umbilical vein endothelial cells in vitro. By conducting a clustering analysis of the amino acid sequences using sequence similarity criteria and of the experimental results using a hierarchical clustering algorithm, we have demonstrated that there is an underlying correlation between the sequence and activity of the identified peptides. This combination of experimental and computational approaches introduces a novel systematic framework for studying peptide activity, identifying novel peptides with anti-angiogenic activity, and designing mimetic peptides with tailored properties. 相似文献
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87.
Summary. Basic biological processes in which tissue transglutaminase (TG2, tTG) is thought to be important including apoptosis, cell
adhesion and migration, ECM homeostasis and angiogenesis are key stages in the multistage tumour progression cascade. Studies
undertaken with primary tumours and experimental models suggest that TG2 expression and activity in the tumour body and surrounding
matrix generally decreases with tumour progression, favouring matrix destabilisation, but supporting angiogenesis and tumour
invasion. In contrast, in the secondary metastatic tumour TG2 is often highly expressed whereby its potential roles in cell
survival both at the intra- and extracellular level become important. In the following review the underlying molecular basis
for the selection of these different phenotypes in tumour types and the anomaly for the requirement of TG2 is discussed in
relation to the complex events of tumour progression. 相似文献
88.
89.
Li Y Sun WG Liu HK Qi GY Wang Q Sun XR Chen BQ Liu JR 《The Journal of nutritional biochemistry》2011,22(12):1127-1136
Antiangiogenic therapy mediated by food components is an established strategy for cancer chemoprevention. Growth factors play critical roles in tumor angiogenesis. A conditioned medium containing growth factors from human gastric adenocarcinoma SGC-7901 cell conditioned medium was used as an angiogenic stimulus in this study. The purpose of this study was to evaluate the inhibitory effect and possible mechanism of γ-tocotrienol on tumor angiogenesis. The results showed that γ-tocotrienol (10-40 μmol/L) significantly suppressed proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) induced by SGC-7901 cell conditioned medium in a dose-dependent manner. γ-Tocotrienol (800-1200 μg/egg) also inhibited new blood vessel formation on the growing chick embryo chorioallantoic membrane in a dose-dependent manner. Moreover, the inhibitory effects of γ-tocotrienol on HUVECs were correlated with inducing the apoptosis and arresting cell cycle at the G0/G1 phase at a dose of 40 μmol/L γ-tocotrienol. In addition, γ-tocotrienol inhibited angiogenesis in HUVECs by down-regulation of β-catenin, cyclin D1, CD44, phospho-VEGFR-2 and MMP-9. The antiangiogenic effects of γ-tocotrienol on HUVECs may be attributable to regulation of Wnt signaling by decreasing β-catenin expression. Thus, our results suggest that γ-tocotrienol has a potential chemopreventive agent via antiangiogenesis. 相似文献
90.
Catalán V Gómez-Ambrosi J Rodríguez A Ramírez B Silva C Rotellar F Hernández-Lizoain JL Baixauli J Valentí V Pardo F Salvador J Frühbeck G 《The Journal of nutritional biochemistry》2011,22(7):634-641