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

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferators (PPs) are an important class of chemicals that act as hepatic tumor promoters in laboratory rodents. The key target for PPs is the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPARalpha) and these chemicals cause cancer by altering the expression of a subset of genes involved in cell growth regulation. The purpose of the present study was to utilize high-density gene expression arrays to examine the genes regulated by the potent PP Wy14,643 (50 microM, 6 h) in both rat (FaO) and human (HepG2) hepatoma cells. Treatment of FaO cells, but not HepG2, revealed the expected fatty acid catabolism genes. However, a larger than expected number of protein kinases, phosphatases, and signaling molecules were also affected exclusively in the FaO cells, including MAPK-phosphatase 1 (MKP-1), Janus-activated kinases 1 and 2 (JAK1 and 2), and glycogen synthetase kinase alpha and beta (GSKalpha and beta). The mRNA accumulation of these genes as well as the protein level for GSK3alpha, JAK1, and JAK2 and MKP-1 activity was corroborated. Due to the importance of MKP-1 in cell signaling, this induction was examined further and was found to be controlled, at least in part, at the level of the gene's promoter. Interestingly, overexpression of MKP-1 in turn affected the constitutive activity of PPARalpha. Taken together, the gene expression arrays revealed an important subset of PP-regulated genes to be kinases and phosphatases. These enzymes not only would affect growth factor signaling and cell cycle control but also could represent feedback control mechanisms and modulate the activity of PPARalpha.
...
PMID:Comprehensive analysis of gene expression in rat and human hepatoma cells exposed to the peroxisome proliferator WY14,643. 1272 18

We demonstrated previously that rat ascites hepatoma MM1 cells require both lysophosphatidic acid (LPA) and fibronectin (FN) for phagokinetic motility and transcellular migration and that these events are regulated through the RhoA-ROCK pathway and tyrosine phosphorylation of proteins including focal adhesion kinase (FAK). Moreover, we reported that palmitoyl-cyclic phosphatidic acid (Pal-cPA), a structural analogue of LPA, inhibits LPA-induced migration of MM1 cells and experimental metastasis of B16 murine melanoma cells. However, the molecular mechanisms of action of Pal-cPA remains to be clarified. To examine this, total cellular lysates after stimulation with LPA or FN were subjected to time-course immunoblot analysis with anti-phophotyrosine and anti-pY397-FAK antibodies. Tyrosine-phosphorylation of FAK especially at Tyr-397 was obviously persistent after stimulation with LPA + FN compared to after stimulation with LPA alone. This persistent phosphorylation was necessary for MM1 cell migration and inhibited by Pal-cPA as by C3 exoenzyme Rho inhibitor. RhoA activity (GTP-bound RhoA) was also measured by the pull down assay using the Rho binding domain of Rhotekin. LPA-induced RhoA-activation of MM1 cells was completely inhibited by Pal-cPA. Moreover, we demonstrated that autophosphorylation of FAK at Tyr-397, downstream of RhoA, contributed to formation of focal adhesions and was critical in LPA-induced MM1 cell migration by developing autophosphorylation-deficient (Y397F) FAK-transfectants. Collectively, Pal-cPA hampered LPA-induced morphological changes and transcellular migration of MM1 cells through downregulating active RhoA and inhibiting its downstream events including autophosphorylation of FAK. Pal-cPA also inhibited endogenous (LPA-independent) activation of RhoA in human fibrosarcoma HT-1080 cells. Pal-cPA may potentially provide a new therapy for the treatment of cancer invasion and metastasis.
...
PMID:Cyclic phosphatidic acid inhibits RhoA-mediated autophosphorylation of FAK at Tyr-397 and subsequent tumor-cell invasion. 1273 90

Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have been reported to exert anti-inflammatory activities in macrophages by competition for transcriptional coactivators with some transcriptional factors, including NF-kappaB. In the present study the influence of PPARgamma activators on IFN-gamma-elicited macrophage stimulation and signaling cascades was investigated. The results show that IFN-gamma-induced inducible NO synthase (iNOS) gene transcription, iNOS protein induction, and NO production are more sensitive to inhibition by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) than by the other two PPARgamma agonists, GW1929 and ciglitazone. Delayed addition of 15dPGJ(2) for 2 h resulted in reduced inhibition, suggesting action by 15dPGJ(2) on the upstream signaling cascades. Immunoblotting, DNA binding, and reporter gene assays consistently revealed the inhibitory ability of 15dPGJ(2), but not GW1929 or ciglitazone, on IFN-gamma-elicited signaling cascades, including tyrosine phosphorylation of Janus tyrosine protein kinase 2 and STAT1, DNA binding, and IFN regulatory factor-1 trans-activation of STAT1. These effects of 15dPGJ(2) were not abrogated by the PPARgamma antagonist, bisphenol A diglycidyl ether, indicating the PPARgamma-independent actions. 15dPGJ(2) also attenuated IL-6-induced tyrosine phosphorylation of STAT1 and STAT3 in Hep3B hepatoma cells. Consistent with the inhibitory effect of reactive oxygen species on STAT1 signaling, STAT1 inhibition by 15dPGJ(2) was abrogated by N-acetylcysteine, glutathione, superoxide dismutase, and catalase. Furthermore, 15dPGJ(2)-induced inhibition of STAT1 phosphorylation and NO production still occurred in the presence of peroxovanadate, ruling out the action mechanism of 15dPGJ(2) on tyrosine phosphatase. Taken together, for the first time in this study we demonstrate that 15dPGJ(2) can inhibit cytokine-stimulated Janus kinase 2-STAT signaling through a PPARgamma-independent, reactive oxygen species-dependent mechanism. These data provide a novel molecular mechanism of iNOS inhibition by 15dPGJ(2) and confirm its physiological role in anti-inflammation.
...
PMID:Inhibition of IFN-gamma-mediated inducible nitric oxide synthase induction by the peroxisome proliferator-activated receptor gamma agonist, 15-deoxy-delta 12,14-prostaglandin J2, involves inhibition of the upstream Janus kinase/STAT1 signaling pathway. 1284 70

Selenium has been shown to sustain the growth of selected human hepatocellular carcinoma cell lines under serum-free conditions, but the detailed mechanism remained undetermined. In the present study, the molecular mechanism(s) involving sodium selenite (Na2SO3, Se) as a survival agent were determined. Selenite not only protects HuH7 cells from serum deprivation-induced apoptosis, it also supports its long-term growth in sodium selenite (10(-7)m) supplemented serum-free medium. The anti-apoptotic effect correlates with activation of focal adhesion kinase and the phosphatidylinositol 3-kinase (PI3K)-Akt kinase pathway. Using HuH7 cells stably transfected with a constitutively active Akt kinase and PI3K inhibitor LY294002, selenite-induced cell survival was shown to be PI3K-Akt-dependent. Parallel changes included a significant reduction in the intracellular reactive oxygen species content, the reversal of DNA fragmentation, and the suppression of caspase and apoptosis signal-regulating kinase 1 activities. HuH7 cells stably expressing a Rac1 mutant N17 (Rac1N17-HuH7) are refractory to selenite treatment. In these cells selenite supplement neither triggers Akt activation nor supports cell proliferation. Participation of Rac1 activation in this event is supported by the fact that selenite treatment drastically enhanced activation of Rac1. The exact link between selenite treatment, Rac1 activation, and activation of the focal adhesion kinase-PI 3-kinase, however, remains to be characterized. The mitogenic signaling mediated by selenite may involve unconventional growth stimuli including higher glutathione peroxidase 1 activity and higher transcription levels of selenoprotein P. The selenium-HuH7 system we have established thus provides a unique tool that will allow the biological role of selenite in growth regulation of hepatocytes to be studied in detail.
...
PMID:Selenite-induced survival of HuH7 hepatoma cells involves activation of focal adhesion kinase-phosphatidylinositol 3-kinase-Akt pathway and Rac1. 1289 80

The effect of insulin on cancer metastatic potential was studied in a human hepatocarcinoma cell line, H7721. Cell adhesion to human umbilical vein endothelial cells (HUVECs) and laminin as well as chemotactic cell migration and invasion were selected as the indices of metastasis-related phenotypes for assessment of metastatic potential ex vivo. The results indicated that insulin enhanced all of these metastasis-related phenotypes. After the cells were treated with specific inhibitor of PI3K (LY294002) or transfected with antisense cDNA of PKB (AS-PKB), all of the above phenotypes were attenuated, and they could not be significantly stimulated by insulin, indicating that the insulin effect on metastatic potential was mediated by PI3K and PKB. Only the monoclonal antibody to the sialyl Lewis X (SLe(x)), but not antibodies to other Lewis antigens, significantly blocked the cell adhesion to HUVECs, cell migration and invasion, suggesting that SLe(x) played a crucial role in the metastatic potential of H7721 cells. The upregulation of cell surface SLe(x) and alpha-1,3-fucosyltransferase-VII (alpha-1,3 Fuc T-VII, enzyme for SLe(x) synthesis) was also mediated by PI3K and PKB, since LY294002 and AS-PKB also reduced the expressions of SLe(x) and alpha-1,3 FucT-VII, and attenuated the response to insulin. Furthermore, the alterations in the expressions of PKB protein and activity were correlated to the changes of metastatic phenotypes and SLe(x) expression. Taken together, the insulin/PKB signalling pathway participated in the enhancement of metastatic potential of H7721 cells, which was mediated by the upregulation of the expression of SLe(x) and alpha-1,3 FucT-VII.
...
PMID:Insulin/protein kinase B signalling pathway upregulates metastasis-related phenotypes and molecules in H7721 human hepatocarcinoma cell line. 1295 Feb 63

Beta1,4-galactosyltransferase1 (beta1,4GT1) is localized both in the Golgi complex and on the cell surface. In our previous study, we first reported that beta1,4GT1 was associated with cycloheximide-induced apoptosis in human hepatocarcinoma cells. In this study, we transfected constitutively active protein kinase B (Gag-PKB), a central mediator of anti-apoptotic signals transduced by the PI3-kinase, into SMMC-7721 human hepatocarcinoma cells, and examined its effect on apoptosis and beta1,4GT1 activity. Flow cytometry analysis showed that apoptosis was inhibited in Gag-PKB transfected SMMC-7721 cells. At the same time, beta1,4GT1 mRNA level and enzyme activities were downregulated in these cells, consistent with which, the content of beta1,4 Gal branch in the glycoconjugates was decreased in stably transfected cells. Cotransfection of beta1,4GT1 promoter/luciferase reporter and Gag-PKB decreased the luciferase reporter activity in a dose-dependent manner, indicating that the differences in mRNA levels might be regulated through promoter function. All these findings suggested that changes of beta1,4GT1 activity might be involved in apoptotic pathway in hepatocarcinoma cells.
...
PMID:Constitutively active PKB/Akt inhibited apoptosis and down-regulated beta1,4-galactosyltransferase 1 in hepatocarcinoma cells. 1295 Oct 46

The endogenous cannabinoid anandamide, a lipid mediator, induces various physiologic events such as vascular relaxation, inhibition of gap-junctions formation, tumor proliferation, neurologic analgesia, and apoptosis. Although increased concentration of anandamide in plasma has been implicated in pathophysiologic states including endotoxin-induced hypotension, the effects of anandamide on hepatocytes still remain unclear. In this study, we present evidence that plasma anandamide concentration is highly increased in severe hepatitis and cirrhosis patients. In addition, concentrations of anandamide within the pathophysiologic range potently induced apoptosis of hepatoma cell line (Hep G2) and primary hepatocytes, suggesting a possible link between increased anandamide level and hepatocyte damage. Anandamide-induced cell death was preceded by G0/G1 cell-cycle arrest, activation of proapoptotic signaling (i.e., p38 MAPK and JNK), and inhibition of antiapoptotic signaling (i.e., PKB/Akt) pathways. Moreover, anandamide increased susceptibility to oxidative stress-induced hepatocyte damage. In this context, methyl-beta-cyclodextrin (MCD), a membrane cholesterol depletor, or mevastatin, an HMG-CoA reductase inhibitor, or N-acetyl cysteine, an antioxidant, potently inhibited the anandamide-induced proapoptotic events and cell death, whereas putative cannabinoid receptor antagonists did not exhibit an inhibitory effect on anandamide-induced cell death. Furthermore, binding assay using polymyxin beads revealed that anandamide could interact with cholesterol. In conclusion, our data suggest that cholesterol present in the cell membrane determines the fate of hepatocytes exposed to anandamide, possibly functioning as an anandamide receptor.
...
PMID:Membrane cholesterol but not putative receptors mediates anandamide-induced hepatocyte apoptosis. 1457 55

We investigated 39 primary hepatocellular carcinomas (HCCs) for aberrations in DNA copy number, using comparative genomic hybridization (CGH). Gain of DNA at 8q was common in these tumors; high-level gains, indicative of gene amplification, occurred most frequently at 8q23-q24. Gains of 8q correlated with large (>5 cm) tumor size. To identify targets of the amplification events involving 8q, we determined expression levels of 14 candidate genes within that region in a total of 41 HCCs by means of real-time quantitative reverse-transcription polymerase chain reactions (RT-PCR). Significant correlation was found between elevated levels of expression and increases in copy number for PTK2 (located at 8q24.3) and EIF3S3 (at 8q23.3), but for none of the other candidates, which included MYC (8q24.1). Southern blot analyses confirmed that PTK2 and EIF3S3 were amplified, respectively, in 5 (19%) and 7 (26%) of the 27 tumors examined in accordance with expression patterns, an indication that expression of PTK2 and EIF3S3 was probably up-regulated by the amplification mechanism. When we analyzed potential relationships between elevated expression of PTK2 and EIF3S3 and clinicopathologic parameters, high expression of the 2 transcripts was significantly associated with large (>5 cm) tumor size and with hepatitis B virus (HBV) infection. In conclusion, PTK2 and EIF3S3, which, respectively, encode focal adhesion kinase and the p40 subunit of the eukaryotic initiation factor 3, were probable targets within the amplification at 8q23-q24 and may be involved in progression of HCC.
...
PMID:PTK2 and EIF3S3 genes may be amplification targets at 8q23-q24 and are associated with large hepatocellular carcinomas. 1457 63

To determine the possible role of the epigenetic mechanisms in carcinogenesis of the hepatocellular carcinoma, we methylation-profiled the promoter CpG islands of twenty four genes both in HCC tumors and the neighboring non-cancerous tissues of twenty eight patients using the methylation-specific PCR (MSP) method in conjunction with the DNA sequencing. In comparison with the normal liver tissues from the healthy donors, it was found that while remained unmethylated the ABL, CAV, EPO, GATA3, LKB1, NEP, NFL, NIS and p27KIP1 genes, varying extents of the HCC specific hypermethylation were found associated with the ABO, AR, CSPG2, cyclin a1, DBCCR1, GALR2, IRF7, MGMT, MT1A, MYOD1, OCT6, p57KIP2, p73, WT1 genes, and demethylation with the MAGEA1 gene, respectively. Judged by whether the hypermethylated occurred in HCC more frequently than in their neighboring normal tissues, the hypermethylation status of the AR, DBCCR1, IRF7, OCT6, and p73 genes was considered as the event specific to the late stage, while that the rest that lacked such a distinguished contrast, as the event specific to the early stage of HCC carcinogenesis. Among all the clinical pathological parameters tested for the association with, the hypermethylation of the cyclin a1 gene was more prevalent in the non-cirrhosis group (P=0.021) while the hypermethylated p16INK4a gene was more common in the cirrhosis group (P=0.017). The concordant methylation behaviors of nineteen genes, including the four previously studied and their association with cirrhosis has been evaluated by the best subgroup selection method. The data presented in this report would enable us to shape our understanding of the mechanisms for the HCC specific loss of the epigenetic stability of the genome, as well as the strategy of developing the novel robust methylation based diagnostic and prognostic tools.
...
PMID:Methylation profiling of twenty four genes and the concordant methylation behaviours of nineteen genes that may contribute to hepatocellular carcinogenesis. 1467 55

Elevated secretion of glucocorticoids (GCs) or hypersensitivity to GCs has a permissive effect on the development of obesity and leads to abnormalities of body fat distribution. Recent studies demonstrated GCs act as antagonists of leptin in rodents. However, little is known about the interaction between GCs and leptin signaling. In the present study, we investigated the effects of GCs on leptin action in vitro and in vivo. GCs rapidly inhibited the leptin-induced STAT3 phosphorylation in a dose- and time-dependent manner, as assayed by Western blotting using anti-phosphospecific-STAT3 in human hepatoma cell lines (Huh7) transiently expressing long form leptin receptor. GCs also inhibited the leptin-induced JAK2 tyrosine phosphorylation but unaltered the specific binding of (125)I-leptin to the cells. Parallel experiments, however, demonstrated that the inhibitory effects of GCs were not observed in either IL-6- or LIF-induced STAT3 phosphorylation. Furthermore, we examined the feeding behavior and hypothalamic leptin signaling following intracerebroventricular (icv) infusion of GCs prior to icv leptin infusion in Sprague-Dawley rats. The food intake after 24 h of icv leptin injection increased 3-fold in GCs-treated animals. In addition, central infusion of GCs resulted in a marked reduction of hypothalamic STAT3 phosphorylation in response to icv infusion of leptin. To clarify the molecular mechanism by which GCs rapidly reduce leptin-induced JAK/STAT signaling, we examined the intracellular signal transduction pathway potentially mediated by GCs. PD98059, a specific MEK inhibitor, blocked the inhibitory effects of GCs on leptin-induced JAK/STAT activation in Huh7 cells. These results suggest GCs antagonize leptin action by a rapid inhibition of the leptin-induced JAK/STAT pathway partly via MAPK cascade.
...
PMID:Rapid inhibition of leptin signaling by glucocorticoids in vitro and in vivo. 1499 17


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---