Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, is the ligand for five specific G protein-coupled receptors, named S1P(1) to S1P(5). In this study, we found that cross-communication between platelet-derived growth factor receptor and S1P(2) serves as a negative damper of PDGF functions. Deletion of the S1P(2) receptor dramatically increased migration of mouse embryonic fibroblasts toward S1P, serum, and PDGF but not fibronectin. This enhanced migration was dependent on expression of S1P(1) and sphingosine kinase 1 (SphK1), the enzyme that produces S1P, as revealed by downregulation of their expression with antisense RNA and small interfering RNA, respectively. Although S1P(2) deletion had no significant effect on tyrosine phosphorylation of the PDGF receptors or activation of extracellular signal-regulated kinase 1/2 or Akt induced by PDGF, it reduced sustained PDGF-dependent p38 phosphorylation and markedly enhanced Rac activation. Surprisingly, S1P(2)-null cells not only exhibited enhanced proliferation but also markedly increased SphK1 expression and activity. Conversely, reintroduction of S1P(2) reduced DNA synthesis and expression of SphK1. Thus, S1P(2) serves as a negative regulator of PDGF-induced migration and proliferation as well as SphK1 expression. Our results suggest that a complex interplay between PDGFR and S1P receptors determines their functions.
Mol Cell Biol 2005 May
PMID:The S1P2 receptor negatively regulates platelet-derived growth factor-induced motility and proliferation. 1587 Feb 93

Neuroendocrine tumors, such as carcinoids, are highly metastatic neoplasms that secrete bioactive hormones resulting in carcinoid syndrome. Few curative treatments exist outside of surgical resection. We have previously shown that activation of the Raf-1 signaling pathway can suppress hormone production in carcinoid tumor cells. In this study, we investigated a novel treatment for carcinoid tumor cell growth based on pharmacologic Raf-1 activation using the compound ZM336372. Treatment of carcinoid tumor cells with ZM336372 resulted in progressive phosphorylation of Raf-1, mitogen-activated protein kinase 1/2, and extracellular signal-regulated kinase 1/2. Importantly, exposure to ZM336372 resulted in a significant reduction of bioactive hormone levels as well as the transcription factor, human achaete-scute homologue-1 in carcinoid tumor cells. Furthermore, treatment with ZM336372 led to a marked suppression of cellular proliferation and induction of the cell cycle inhibitors p21 and p18. In summary, ZM336372 targets both proliferation and palliative issues associated with carcinoid tumor cells, and therefore, warrants further investigation as a possible therapeutic strategy for patients with carcinoid tumors.
Mol Cancer Ther 2005 Jun
PMID:ZM336372, a Raf-1 activator, suppresses growth and neuroendocrine hormone levels in carcinoid tumor cells. 1595 48

Insulin-like growth factor-I receptor (IGF-IR) plays an important role in tumor cell growth and survival. On ligand stimulation, IGF-IR, a receptor tyrosine kinase, phosphorylates tyrosine residues on two major substrates, IRS-1 and Shc, which subsequently signal through the Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways. Here, we describe the characterization of a fully human anti-IGF-IR monoclonal antibody 19D12 that inhibits IGF binding and autophosphorylation of both IGF-IR/IGF-IR homodimers and IGF-IR/insulin receptor heterodimers. 19D12 does not recognize insulin receptor homodimers. In addition to inhibiting IGF-IR autophosphorylation, 19D12 also inhibits IRS-1 phosphorylation and activation of the major downstream signaling molecules AKT and extracellular signal-regulated kinase 1/2. Furthermore, the antibody down-regulates the total IGF-IR protein level and can exhibit antibody-dependent cellular cytotoxicity activity against a non-small cell adenocarcinoma cell line in vitro in the presence of isolated human natural killer cells. 19D12 binds tightly to the receptor, with an affinity of 3.8 pmol/L as measured by KinExA. In cell culture, 19D12 inhibits proliferation and soft agar growth of various tumor cell lines. In vivo, 19D12 inhibits the tumor growth of a very aggressive human ovarian tumor xenograft model A2780. These data support the development of this anti-IGF-IR monoclonal antibody as a promising anticancer agent.
Mol Cancer Ther 2005 Aug
PMID:Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody. 1609 37

The root of Stellera chamaejasme L. is a traditional Chinese herb termed Rui Xiang Lang Du and has been used to treat solid tumors, tuberculosis and psoriasis. Exactly how S. chamaejasme L. regulates cellular responses remains unclear. We examined four biflavonoids isolated from S. chamaejasme L., including isochamaejasmin, two of its stereo-isomers and a methyl derivative, in functional assays originally designed to screen ligands for the G protein-coupled formyl peptide receptor-like 1 (FPRL1). Isochamaejasmin was found to induce the expression of a nuclear factor (NF)-kappaB-directed reporter gene in transfected HeLa cells with an EC50 of 3.23 microM, independently of FPRL1. The isochamaejasmin-stimulated NF-kappaB reporter activity was accompanied by nuclear translocation of NF-kappaB proteins and was blocked by a dominant-negative construct of IkappaBalpha. Isochamaejasmin also induced time-dependent phosphorylation of the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 and p38, and a novel protein kinase C (PKCdelta). Likewise, inhibition of these kinases with the respective pharmacological inhibitors significantly reduced the isochamaejasmin-stimulated NF-kappaB activation. It is noteworthy that the two stereoisomers and the methyl derivative did not induce detectable activation of NF-kappaB and were more cytotoxic than isochamaejasmin, which could partially rescue cycloheximide-induced apoptosis. Inhibition of NF-kappaB activation reversed the anti-apoptotic effect of isochamaejasmin. These results provide the first evidence for a potential mechanism of action by S. chamaejasme L., and indicate that structurally similar compounds derived from S. chamaejasme L. may have different pharmacological properties.
Mol Pharmacol 2005 Dec
PMID:Stereospecific induction of nuclear factor-kappaB activation by isochamaejasmin. 1614 13

Skeletal disorders and neural tube closure defects represent clinically significant human malformations. The signaling networks regulating normal skeletal patterning and neurulation are largely unknown. Targeted mutation of the active site lysine of MEK kinase 4 (MEKK4) produces a kinase-inactive MEKK4 protein (MEKK4(K1361R)). Embryos homozygous for this mutation die at birth as a result of skeletal malformations and neural tube defects. Hindbrains of exencephalic MEKK4(K1361R) embryos show a striking increase in neuroepithelial cell apoptosis and a dramatic loss of phosphorylation of MKK3 and -6, mitogen-activated protein kinase kinases (MKKs) regulated by MEKK4 in the p38 pathway. Phosphorylation of MAPK-activated protein kinase 2, a p38 substrate, is also inhibited, demonstrating a loss of p38 activity in MEKK4(K1361R) embryos. In contrast, the MEK1/2-extracellular signal-regulated kinase 1 (ERK1)/ERK2 and MKK4-Jun N-terminal protein kinase pathways were unaffected. The p38 pathway has been shown to regulate the phosphorylation and expression of the small heat shock protein HSP27. Compared to the wild type, MEKK4(K1361R) fibroblasts showed significantly reduced phosphorylation of p38 and HSP27, with a corresponding heat shock-induced instability of the actin cytoskeleton. Together, these data demonstrate MEKK4 regulation of p38 and that substrates downstream of p38 control cellular homeostasis. The findings are the first demonstration that MEKK4-regulated p38 activity is critical for neurulation.
Mol Cell Biol 2005 Oct
PMID:Ablation of MEKK4 kinase activity causes neurulation and skeletal patterning defects in the mouse embryo. 1619 73

Estrogen receptors (ERs) stimulate genomic effects by acting as nuclear transcription factors as well as non-genomic effects by activating distinct cytoplasmic protein kinase cascades. Non-genomic effects have been implicated in numerous cellular processes, such as proliferation, differentiation, apoptosis and vasorelaxation. To exploit non-genomic effects mediated by ERalpha for novel hormone replacement regimens, we screened a focused library of steroid receptor ligands to identify compounds exhibiting properties different from estradiol, i.e. substances that selectively stimulate non-genomic signal transduction pathways while exhibiting low genomic activities. Treatment of breast cancer cells and osteosarcoma cells with estradiol, estren, substance A and substance B led to non-genomic activation of Akt (protein kinase B) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascades mediated by Src (Rous Sarcoma Virus, non-receptor tyrosine kinase) and phosphatidylinositol-3-kinase (PI3K) stimulation. Such compounds leading to prominent Akt/ERK activation but exhibiting only weak genomic properties were applied in vasorelaxation assays, modeling physiological non-genomic ER responses. As expected from PI3K and Src activation data, substances were as effective as estradiol in mediating vasorelaxation. We assume that these pathway-selective estrogen receptor ligands may serve as potent lead structures for novel hormone replacement strategies exhibiting lesser side effects than the existing treatment paradigms.
J Steroid Biochem Mol Biol 2006 Jan
PMID:Identification of estrogen receptor ligands leading to activation of non-genomic signaling pathways while exhibiting only weak transcriptional activity. 1620 30

Hypoxia-inducible factor-1alpha (HIF-1alpha) is overexpressed in many human tumors and their metastases, and is closely associated with a more aggressive tumor phenotype. In this study, we investigated the effect of resveratrol, a natural product commonly found in grapes and various other fruits, on hypoxia-induced HIF-1alpha protein accumulation and vascular endothelial growth factor (VEGF) expression in human tongue squamous cell carcinomas and hepatoma cells. Our results showed that resveratrol significantly inhibited both basal level and hypoxia-induced HIF-1alpha protein accumulation in cancer cells, but did not affect HIF-1alpha mRNA levels. Pretreatment of cells with resveratrol significantly reduced hypoxia-induced VEGF promoter activities and VEGF expression at both mRNA and protein levels. The mechanism of resveratrol inhibition of hypoxia-induced HIF-1alpha accumulation seems to involve a gradually shortened half-life of HIF-1alpha protein caused by an enhanced protein degradation through the 26S proteasome system. In addition, resveratrol remarkably inhibited hypoxia-mediated activation of extracellular signal-regulated kinase 1/2 and Akt, leading to a marked decrease in hypoxia-induced HIF-1alpha protein accumulation and VEGF transcriptional activation. Functionally, we observed that resveratrol also significantly inhibited the hypoxia-stimulated invasiveness of cancer cells. These data suggested that HIF-1alpha/VEGF could be a promising drug target for resveratrol in the development of an effective chemopreventive and anticancer therapy in human cancers.
Mol Cancer Ther 2005 Oct
PMID:Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1alpha and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells. 1622 95

To understand how type I and II endometrial tumors uniquely respond to tyrosine kinase inhibitor treatments, we evaluated the signaling pathways of epidermal growth factor (EGF) receptor (EGFR) under the effects of EGF and Iressa (ZD1839, gefitinib) using Ishikawa H and Hec50co cells that model type I and II endometrial carcinomas, respectively. The cells were assayed for the expression of EGFR and both cell lines express an average of 100,000 EGFR per cell; however, Ishikawa H cells express higher levels of HER-2/neu compared with Hec50co cells (1.38 x 10(5) compared with 2.04 x 10(4), respectively). Using the Kinetworks multi-immunoblotting approach, which profiles 31 signaling phosphoproteins, the most striking result was that Hec50co cells show a higher number of basal phosphorylated sites compared with Ishikawa H cells. Furthermore, we identified targets of Iressa treatment in both cell lines. Iressa, at a dose of 1 micromol/L, blocked the autophosphorylation of EGFR in Ishikawa H and Hec50co cells with some distinctive effects on downstream effectors. Nevertheless, in both cell lines, EGF stimulated and Iressa blocked the major EGFR target mitogen-activated protein kinases extracellular signal-regulated kinase 1 and 2 equally. The high basal phosphorylation of numerous signaling molecules in Hec50co cells that were not inhibited by Iressa indicates that other growth factor pathways are active in addition to EGFR. We conclude that endometrial cancer cells that model type I and II carcinomas have the capacity to respond to EGFR inhibition as a therapeutic strategy; however, the response of the more aggressive type II tumors may be limited by the constitutive activation of other signaling pathways.
Mol Cancer Ther 2005 Dec
PMID:Regulation of signaling phosphoproteins by epidermal growth factor and Iressa (ZD1839) in human endometrial cancer cells that model type I and II tumors. 1637 4

The aim of this article was to investigate the signalling pathways involved in metalloproteinase-9 (MMP-9) expression induced by tumour necrosis factor-alpha (TNF-alpha) in first-trimester trophoblastic cells. TNF-alpha-induced MMP-9 expression, secretion and activity were completely blocked by stress-activated protein kinase/jun kinase (SAPK/JNK) and Erk inhibitors (SP600 125 and U0126 respectively) but not by p38 mitogen-activated protein kinase (MAPK) inhibitors (SB203 580 and SB202 190). Stimulation of HIPEC 65 cells with TNF-alpha caused phosphorylation of JNK and extracellular signal-regulated kinase 1/2 (Erk1/2), with a peak after 20 min of treatment. Transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1)-binding site were identified as the cis-elements involved in TNF-alpha activation as determined by electromobility shift assays. TNF-alpha-induced transactivation of NF-kappaB was inhibited by U0126, whereas TNF-alpha-induced transactivation of AP-1 was inhibited by SP600 125. Taken together, these results indicate that in trophoblastic cells, TNF-alpha probably activates two different pathways leading to MMP-9 expression: (a) Erk1/2 pathway which in turn initiates NF-kappaB activation and (b) SAPK/JNK pathway that activates AP-1.
Mol Hum Reprod 2006 Apr
PMID:Involvement of MAPK pathway in TNF-alpha-induced MMP-9 expression in human trophoblastic cells. 1652 Mar 44

The insulin-like growth factor 1 receptor (IGF-1R) is a multifunctional receptor that mediates signals for cell proliferation, differentiation, and survival. Genetic experiments showed that IGF-1R inactivation in skin results in a disrupted epidermis. However, because IGF-1R-null mice die at birth, it is difficult to study the effects of IGF-1R on skin. By using a combined approach of conditional gene ablation and a three-dimensional organotypic model, we demonstrate that IGF-1R-deficient skin cocultures show abnormal maturation and differentiation patterns. Furthermore, IGF-1R-null keratinocytes exhibit accelerated differentiation and decreased proliferation. Investigating the signaling pathway downstream of IGF-1R reveals that insulin receptor substrate 2 (IRS-2) overexpression compensates for the lack of IGF-1R, whereas IRS-1 overexpression does not. We also demonstrate that phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1 and 2 are involved in the regulation of skin keratinocyte differentiation and take some part in mediating the inhibitory signal of IGF-1R on differentiation. In addition, we show that mammalian target of rapamycin plays a specific role in mediating IGF-1R impedance of action on keratinocyte differentiation. In conclusion, these results reveal that IGF-1R plays an inhibitory role in the regulation of skin development and differentiation.
Mol Cell Biol 2006 Apr
PMID:Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation. 1653 11


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