Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

VEGF, Hedgehog, FGF, Notch, and WNT signaling pathways network together for vascular remodeling during embryogenesis, tissue regeneration, and carcinogenesis. VEGFA (VEGF), VEGFB, VEGFC, VEGFD (FIGF) and PGF (PlGF) are VEGF family ligands for receptor tyrosine kinases, including VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4). Bevacizumab (Avastin), Sunitinib (Sutent) and Sorafenib (Nexavar) are anti-cancer drugs targeted to VEGF signaling pathway. TCF/LEF binding sites within the promoter region of human VEGF family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were identified within the 5'-promoter region of human VEGFD gene within AC095351.5 genome sequence, comparative genomics analyses on VEGFD orthologs were further performed. ASB9-ASB11-VEGFD locus at human chromosome Xp22.2 and ASB5-VEGFC locus at human chromosome 4q34 were paralogous regions within the human genome. Human VEGFD mRNA was expressed in lung, small intestine, uterus, breast, neural tissues, and neuroblastoma. Mouse Vegfd mRNA was expressed in kidney, pregnant oviduct, and neural tissues. Chimpanzee VEGFD promoter, cow Vegfd promoter, mouse Vegfd promoter and rat Vegfd promoter were identified within NW_121675.1, AC161065.2, AL732475.6 and AC130036.3 genome sequences, respectively. Three out of four TCF/LEF-binding sites within human VEGFD promoter were conserved in chimpanzee VEGFD promoter, and one in cow Vegfd promoter. TCF/LEF-binding site, not conserved in human VEGFD promoter, occurred in cow, mouse and rat Vegfd promoters. At least five out of six bHLH-binding sites within human VEGFD proximal promoter region were conserved in chimpanzee VEGFD proximal promoter region, while only one in cow Vegfd proximal promoter region. Together these facts indicate that relatively significant promoter evolution occurred among mammalian VEGFD orthologs. Human VEGFD was characterized as a potent target gene of WNT/beta-catenin signaling pathway. VEGFD, implicated in angiogenesis and lymphatic metastasis, is a pharmacogenomics target in the field of oncology.
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PMID:Comparative integromics on VEGF family members. 1668 60

Metastasis is the principal cause of cancer mortality, with the lymphatic system being the first route of tumor dissemination. The glycoproteins VEGF-C and VEGF-D are members of the vascular endothelial growth factor (VEGF) family, whose role has been recently recognized as lymphatic system regulators during embryogenesis and in pathological processes such as inflammation, lymphatic system disorders and malignant tumor metastasis. They are ligands for the VEGFR-3 receptor on the membrane of the lymphatic endothelial cell, resulting in dilatation of existing lymphatic vessels as well as in vegetation of new ones (lymphangiogenesis). Their determination is feasible in the circulating blood by immunoabsorption and in the tissue specimen by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Experimental and clinicopathological studies have linked the VEGF-C, VEGF-D/VEGFR3 axis to lymphatic spread as well as to the clinical outcome in several human solid tumors. The majority of these data are derived from surgical specimens and malignant cell series, rendering their clinical application questionable, due to subjectivity factors and post-treatment quantification. In an effort to overcome these drawbacks, an alternative method of immunodetection of the circulating levels of these molecules has been used in studies on gastric, esophageal and colorectal cancer. Their results denote that quantification of VEGF-C and VEGF-D in blood samples could serve as lymph node metastasis predictive biomarkers and contribute to preoperative staging of gastrointestinal malignancies.
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PMID:Circulating lymphangiogenic growth factors in gastrointestinal solid tumors, could they be of any clinical significance? 1846 54

The human VEGF family consists of VEGF (VEGF-A), VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF). The VEGF family of receptors consists of three protein-tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3) and two non-protein kinase co-receptors (neuropilin-1 and neuropilin-2). These components participate in new blood vessel formation from angioblasts (vasculogenesis) and new blood vessel formation from pre-existing vasculature (angiogenesis). Interaction between VEGFR1 and VEGFR2 or VEGFR2 and VEGFR3 alters receptor tyrosine phosphorylation.
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PMID:VEGF receptor protein-tyrosine kinases: structure and regulation. 1868 Jul 22

Vascular endothelial growth factor (VEGF)-C and VEGF-D belong to the VEGF family, and are thought to be involved in lymphangiogenesis and angiogenesis. At present, this is the only known system that can induce lymphatic vessel growth in the body. However, the roles of VEGF-C and VEGF-D in breast cancer tissue have not been clarified. In the present study, we measured the mRNA expression of VEGF-C and VEGF-D in the breast cancer tissue of 109 patients by real-time polymerase chain reaction (RT-PCR). Between non-infiltrating breast cancer (n=6) and infiltrating breast cancer (n=103), there were no significant differences in the mRNA expression of VEGF-C and VEGF-D. In infiltrating cancer, the expression of HER2 exhibited a positive correlation to VEGF-C and VEGF-D mRNA expression (p=0.027, p=0.048). However, mRNA expression ofVEGF-C and VEGF-D did not exhibit any significant correlation to lymphatic vessel invasion or lymph node metastasis. Among patients without lymph node metastasis, the mRNA expression of VEGF-C and VEGF-D for patients with lymphatic vessel invasion was significantly higher than that for patients without lymphatic vessel invasion (p=0.001, p=0.050). The results suggest that, in breast cancer, VEGF-C and VEGF-D are involved in lymphatic vessel invasion prior to lymph node metastasis, and their expression decreases after lymph node metastasis occurs.
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PMID:Role of vascular endothelial growth factor-C and -D mRNA in breast cancer. 1871 90

Adipose tissue-derived stem cells (ADSC) are isolated from the stromal vascular fraction (SVF) of adipose tissue and considered an excellent cell source for regenerative medicine. During the isolation and propagation of several human ADSC cell lines, we observed the emergence of an unusual cell line designated HADSC-6. Although initially fibroblast-like as typical ADSC are, HADSC-6 cells became homogeneously cuboid in shape, had very little cytoplasm, and formed aggregates with capsule-like boundary. Proliferation assay showed that HADSC-6 grew much faster than typical HADSC cell lines, such as HADSC-20. Immunocytochemistry showed that HADSC-6 did not express endothelial markers CD31 and vWF, and matrigel tube formation assay showed that it was unable to form endothelial-like tube structures. However, LDL uptake, a reliable endothelial marker, was positively identified. Chromosomal analysis showed that HADSC-6 cells were hypertriploid, and soft agar colony formation assay showed that they were able to proliferate and form large colonies in an anchorage-independent manner. However, tumorigenicity test showed that HADSC-6 was unable to form tumors in athymic mice. RT-PCR analysis showed that both HADSC-6 and HADSC-20 expressed VEGF-A, VEGF-B, VEGF-D, and VEGFR1 but not VEGFR2 or VEGFR3. VEGF-C, however, was expressed at a high level in HADSC-20 but undetectable in HADSC-6. In the IGF system, IGF-1 was abundantly expressed in HADSC-20 but marginally detectable in HADSC-6, and IGF-1R was abundantly expressed in HADSC-6 but not detectable in HADSC-20. In the FGF system, bFGF was abundantly expressed in HADSC-20 but marginally detectable in HADSC-6, and FGFR1 was abundantly expressed in both. Taken together, these results suggested that HADSC-6 cells were spontaneously transformed from the endothelium; therefore, they were further compared to previously published data of four naturally occurring human angiosarcoma cell lines. The results showed that the established angiosarcoma cell lines exhibit considerable variations among themselves and HADSC-6 displayed most of these variable characteristics.
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PMID:Identification of an aberrant cell line among human adipose tissue-derived stem cell isolates. 1928 77

Human anal canal squamous cell carcinoma (SCC) cell line has not yet been reported due to the rarity of this disease. Since cell lines to study this malignancy were not available, we attempted to establish and characterize anal canal SCC cell line from primary culture of lymph node metastasis. Six sublines were cloned and isolated from parental cells. They were designated as SaTM-1A, B, C, D, E and F. The features of the six sublines were characterized by reverse transcription-PCR, chemosensitivity test to 5-Fu and CDDP, immunohistochemistry, cDNA microarray analysis and tumorigenicity using immunodeficient mice. All sublines were proliferated in multiple layers at an average doubling time of 24.5 h. VEGF-A, -B, VEGFR-1, -R3 and EGFR were expressed in all sublines, whereas VEGF-D and EGF were not detected in all. SaTM-1 was proven to retain the characteristics of SCC by detection of p63 and cytokeratin 5/6. The cytotoxic effects of 5-Fu were almost similar, although those of CDDP showed different behavior, which was divided into two groups (SaTM-1A, B, E and SaTM-1C, D, F). The differences in gene expression between two groups were analyzed according to susceptibility to cytotoxic effects of CDDP. Thirty-six genes were successfully identified, which may be potentially associated with CDDP resistance. SaTM-1 cells formed tumors easily in vivo, therefore all subclones had tumorigenic property. This is the first report of successful establishment and characterization of a human anal canal SCC cell line, which may provide beneficial resources for investigating the biological features of human anal canal SCC.
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PMID:Establishment and characterization of the human SaTM-1 anal canal squamous cell carcinoma cell line derived from lymph node metastasis. 1972 86

The vascular endothelial growth factors are key mediators of angiogenesis and are also related to several physiological processes such as monocyte chemotaxis, dendritic cell development, hematopoietic stem cell survival, and many others. PlGF, VEGF, VEGFB, VEGFC and VEGFD were identified as members of the vascular endothelial growth factor family. They act by differential activation of three receptors: Flt-1, KDR and Flt-4. PlGF and VEGFB only activate Flt-1. VEGF activates both Flt-1 and KDR. VEGFC and VEGFD activate KDR and Flt-4. The available three dimensional structures of VEGF and PlGF, in complex with the domain-2 of Flt-1, show that both proteins bind in a very similar way to Flt-1 receptor. Here we construct the three dimensional model of the domain-2 of KDR receptor using the same domain of Flt-1 as template. We also construct the model complexes VEGF/KDR, VEGFB/Flt-1, VEGFB/KDR and PlGF/KDR. Molecular dynamics simulations with explicit solvent are carried out on eleven molecular systems: unbound VEGF, VEGF/Flt-1(D2), VEGF/KDR(D2), unbound PlGF, PlGF/Flt-1(D2), PlGF/KDR(D2), unbound VEGFB, VEGFB/Flt-1(D2), VEGFB/KDR(D2), unbound Flt-1(D2) and unbound KDR(D2). We analyze protein-protein interactions, shape complementarity, charge complementarity and hydrogen bonds. As a coarse estimation of the desolvation penalties, we assume a correlation to the number of hydrogen bonds with solvent molecules that are lost upon complex formation. The results herein are consistent with the experimental selectivity profile (VEGF being able to activate both Flt-1 and KDR receptors while VEGFB and PlGF being only able to activate Flt-1), and provide a collection of evidences sustaining the complementarity of polar interactions as the main responsible for protein recognition and selectivity.
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PMID:Investigating the differential activation of vascular endothelial growth factor (VEGF) receptors. 1973 78

Angiogenesis, lymphangiogenesis and vascular maturation occur on a regular, physiological basis in human endometrium. These processes form part of a continuum of vascular remodelling involving numerous regulatory factors. Key factors include vascular endothelial growth factor (VEGF)A, VEGFC and VEGFD, and their associated receptors VEGFR1, VEGFR2 and VEGFR3. A second group of vascular regulatory proteins belongs to the angiopoietin (ANG)-TIE system. Although members of the VEGF family and the ANG-TIE system are represented in the endometrium, our understanding of how these different molecules interact to regulate remodelling of the blood and lymphatic vasculature present in the endometrium is still limited. A review of the current information is provided.
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PMID:Regulation of endometrial vascular remodelling: role of the vascular endothelial growth factor family and the angiopoietin-TIE signalling system. 1975 82

To date, there have been no detailed studies on the lymphatic system in the primate corpus luteum (CL); early reports suggested that the presence of this "secondary circulation" in luteal tissue is species-dependant. Therefore, studies were designed to determine if (a) lymphatic vessels exist, and (b) recently discovered lymphangiogenic factors and their receptor are expressed in the macaque CL during the menstrual cycle. Immunohistochemistry (IHC) detected the lymphatic endothelial cell marker, lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), in some endothelial cells and vessels within the ovarian stroma and theca layer of preovulatory follicles and in the CL. Dual fluorescent IHC demonstrated that LYVE1 co-localized with another lymphatic endothelial cell marker D2-40, but a blood vascular endothelial cell marker (von Willebrand Factor, VWF) was in different cells. The numbers and staining intensity of LYVE1-positive cells in the CL appeared to increase from early to mid luteal phase, and remained elevated thereafter. RT-PCR detected cDNA fragments for mRNAs encoding VEGFC, FIGF, and their receptor FLT4 in CL. Real-time PCR analyses revealed similar patterns of VEGFC and FLT4 expression during the luteal lifespan; mRNA levels increased (p < 0.05) from early to mid luteal phase and decreased (p < 0.05) by late luteal phase. In contrast, FIGF levels were elevated initially, declined (p < 0.05) at mid luteal phase, and then increased (p < 0.05) to very late luteal phase. The data strongly suggest that lymphatic vessels are present in the primate CL, and that the VEGFC/FIGF-FLT4 system regulates lymphangiogenesis and luteal structure-function during the menstrual cycle.
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PMID:Existence of the lymphatic system in the primate corpus luteum. 1977 4

Numerous past studies have suggested a critical role of the paracrine effect between tumor vascular endothelial growth factor (VEGF)-C and lymphatic FLT-4 in solid tumor-associated lymphangiogenesis. In contrast, the pathophysiological role of tumor cell-associated FLT-4 in tumor progression remains to be elucidated. Here, we investigated this role using a tumor implantation model. SAS cells, an oral squamous carcinoma cell line expressing both VEGF-C and FLT-4 but neither FLK-1/KDR nor VEGF-D were adopted for experiments. Stable transformants of dominant-negative (dn) SAS cells were established in which the cytoplasmic domain-deleted FLT-4 was exogenously overexpressed, which can lead to inactivation of endogenous FLT-4 through competitive antagonism and is associated with down-activation of endogenous FLT-4-related intracellular signals. In vitro and in vivo proliferation assays showed lower proliferative activity of dn-SAS cells. An immunohistochemical study revealed that the tumor lymphangiogenesis was significantly suppressed, and the level of human VEGF-C mRNA was significantly lower in dn-SAS cell-derived tumor tissues. Moreover, in vitro studies demonstrated that the significant suppression of VEGF-C and VEGF-A expression was evident in dn-SAS cells or wild-type SAS cells treated with either the FLT-4 kinase inhibitor MAZ51 or the inhibitor of FLT-4-related signals. These findings together suggested that the VEGF-C/FLT-4 autocrine loop in tumor cells was a potential enhancer system to promote cancer progression, and FLT-4 in tumor tissue might become an effective target for cancer therapy.
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PMID:Autocrine loop between vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in oral squamoid cancer cells. 1977 39


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