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)

The virulence of Candida albicans strains deficient in fatty acid synthase activity by virtue of disruption/deletion of the FAS2 gene was examined in a rat model of oropharyngeal candidiasis. The FAS2 alleles of C. albicans CAI4 (delta ura3::imm434/delta ura3::imm434) were sequentially disrupted with a cassette that included a portion of FAS2 from which a 984 bp fragment containing the FAS condensing reaction domain was deleted and replaced with hisG-URA3-hisG sequences. Verification of fatty acid synthase inactivation was obtained from assays of enzyme activity. Strains in which a single allele was disrupted (CFD1 and CFD3) exhibited an approximately 20% reduction in activity, when compared to wild-type. In addition, fatty acid synthase activity was abolished in a FAS2 null mutant strain (CFD2), and growth of CFD2 occurred only when the growth medium was supplemented with Tween 40 and certain fatty acids. Strain CFD2 was avirulent in the rat model, indicating that fatty acid synthase activity is required for C. albicans oropharyngeal infection. Strains with a single FAS2 allele disruption colonized the oral cavity, but the number of cells recovered from infected animals was approximately fivefold less than for the parental strain. The results suggest that FAS may be exploited as a possible target for the development of new antifungal agents.
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PMID:Requirement for the Candida albicans FAS2 gene for infection in a rat model of oropharyngeal candidiasis. 882 18

GH exerts adipogenic activity in several preadipocyte cell lines, whereas in primary rat preadipocytes, GH has an antiadipogenic activity. To better understand the molecular mechanism involved in adipocyte differentiation, the expression of adipocyte-specific genes was analyzed in differentiating preadipocytes in response to GH. We found that the expression of both adipocyte determination and differentiation factor 1 (ADD1) and peroxisome proliferator activated receptor gamma(PPARgamma) was induced in preadipocytes during differentiation. In the presence of GH, which markedly inhibited triglyceride accumulation, no reduction in the expression level of ADD1 was observed in response to GH, whereas there was a 50% reduction in the expression of PPARgamma. The DNA binding activity of the PPARgamma/retinoid X receptor-alpha(RXRalpha) to the ARE7 element from the aP2 gene was also reduced by approximately 50% in response to GH. GH inhibited the expression of late markers of adipocyte differentiation, fatty acid synthase, aP2, and hormone-sensitive lipase by 70-80%. The antiadipogenic effect of GH was not affected by the mitogen-activated protein (MAP) kinase/ extracellular-regulated protein (ERK) kinase inhibitor PD 98059, indicating that the mitogen-activated protein kinase pathway was not involved in GH inhibition of preadipocyte differentiation. The expression of preadipocyte factor-1/fetal antigen 1 was decreased during differentiation, and GH treatment prevented this down-regulation of Pref1/FA1. A possible role for Pref-1/FA1 in mediating the antiadipogenic effect of GH was indicated by the observation that FA1 inhibited differentiation as effectively as GH. These data suggest that GH exerts its inhibitory activity in adipocyte differentiation at a step after the induction of ADD1 but before the induction of genes required for terminal differentiation.
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PMID:Characterization of the inhibitory effect of growth hormone on primary preadipocyte differentiation. 971 40

HER2 (erbB2/neu) is a member of the erbB family of receptor tyrosine kinases and is involved in regulating the growth of several types of human carcinomas. HER2 represents a successful therapeutic target of the biotechnology era as exemplified by the drug Herceptin (trastuzumab), which has clinical activity in a subset of breast cancer patients. Using DNA microarrays, we identified a cohort of genes that are differentially regulated by HER2 in breast epithelial cells. One of the HER2-regulated genes discovered was fatty acid synthase (FAS), which has been shown to be overexpressed in breast cancer as well as other cancers. FAS is implicated in tumorigenesis through its role in cell proliferation and membrane lipid incorporation of neoplastic cells. Here, we demonstrate that HER2-mediated induction of FAS is inhibitable by Herceptin and tyrosine kinase inhibitors of HER2. Through a phosphatidylinositol 3'-kinase-dependent pathway, HER2 stimulates the FAS promoter and ultimately mediates increased fatty acid synthesis. Interestingly, pharmacological inhibition of FAS preferentially induced apoptosis of HER2-overexpressing breast epithelial cells relative to matched vector control cells. These studies characterize a molecular connection between two genes individually implicated in tumorigenesis but never linked together.
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PMID:Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis. 1251 89

High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions of the colon, stomach, esophagus, oral cavity, prostate, and breast. Inhibition of FAS with C75 has led to a significant antitumor effect in both human breast and prostate cancer xenografts. Recently, HER2/neu, which has also been identified in preneoplastic breast lesions, has been shown to regulate FAS expression through the PI3K/Akt signal transduction pathway rendering them susceptible to FAS inhibition. Utilizing the neu-N transgenic mouse model of mammary cancer, weekly treatment of the neu-N mice with C75 (30 mg/kg) for 10 weeks significantly delayed tumor progression. Only 20% of the C75-treated transgenic mice developed mammary carcinoma by 220 days, compared to 50% in the vehicle control animals. Two C75-treated animals never developed mammary cancer. Analysis of mammary tissue following 10 weeks of C75 treatment revealed a significant delay in mammary maturation as manifested by a reduction of the number and caliber of mammary ducts and budding epithelial structures. Apoptotic changes were increased, DNA synthesis was decreased, and the expressions of FAS, neu, Akt, phospho-Akt, and p21(waf1) were all decreased when compared to vehicle controls and FVB/N mice. Importantly, these effects were restricted to the breast epithelial cells that overexpressed neu, not involving other normal duct structures in the skin, liver, or kidney. C247, an FAS inhibitor chemically distinct from C75, significantly delayed mammary maturation similar to C75. Thus, pharmacological inhibition of FAS affects the expression of key oncogenes involved in both cancer development and maintenance of the malignant phenotype. Moreover, these data identify FAS as a potential novel drug target for breast cancer chemoprevention.
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PMID:Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. 1548 85

The hyperactivation of fatty acid synthase (FAS)-catalyzed de novo biosynthesis of fatty acids is a molecular marker linked to tumor virulence in population studies of human malignancies. This activation appears to be linked to neoplastic transformation, since high levels of FAS have also been identified in pre-malignant lesions. This dependence of cancer upon accelerated lipogenesis differs from normal human tissues, in which FAS is suppressed by the presence of small amounts of fatty acids in the diet. The molecular mechanisms by which cancer cells constitutively exhibit FAS overexpression and hyperactivity have begun to emerge. The active involvement of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (MAPK ERK1/2) and phosphatidylinositol-3'-kinase (PI-3'K)/protein kinase B (AKT) transduction cascades in the overexpression of FAS has been recently demonstrated in several cancer cell models. Strikingly, insulin-regulated stimulation of FAS expression in adipose cells is also mediated by the PI-3'K pathway with AKT being involved as a downstream effector. Moreover, FAS overexpression in tumor cells has been demonstrated to occur through a modification of the transcription factor sterol regulatory element-binding protein-1c (SREBP-1c), the major regulatory factor of FAS in liver and adipose tissues, which, in turn, is known to be regulated by MAPK ERK1/2 and PI-3'K/AKT pathways. Therefore, the signal transduction pathways regulating FAS expression in normal and cancer cells seem to share several downstream elements. However, the upstream mechanisms controlling FAS expression in cancer cells must be different from those in normal tissues, since tumor-associated FAS expression seems to be insensitive to nutritional signals. In pre-neoplastic lesions, we hypothesize that the early activation of FAS in pre-malignant cells represents a survival strategy which occurs to compensate for an insufficiency of both oxygen and dietary fatty acids due to, e.g., lack of angiogenesis. Thus, FAS activation reflects an epigenetic dysregulation of the lipogenic pathway in response to the microenvironment of tumors containing regions of poor oxygenation. Upon this unusual metabolic situation, FAS up-regulation also represent a metabolic strategy to maintain high proliferation rates of surviving cells in the absence of exogenous dietary fatty acids. Concomitantly, a variety of oncogenic changes (H-ras, erb B-2, etc.) may result in the constitutive activation of MAPK and PI-3'K/AKT signaling cascades, which, in turn, can activate SREBP-1c and, subsequently, tumor-associated FAS-catalyzed endogenous lipogenesis. Thereafter, high levels of FAS are maintained in coordination with increased demand for fatty acid metabolism and/or membrane synthesis in response to cancer-related overexpression of growth factors (e.g., EGF, heregulin) and/or growth factor receptors (e.g., EGFR, Her-2/neu). The aberrant MAPK and PI-3'K/AKT cascades driven by these oncogenic changes subvert the downregulatory effects of physiological concentrations of dietary fatty acids, resulting in a cancer-associated FAS insensitivity to nutritional signals. This model does not exclude that fundamental differences in the ability of FAS gene to respond to normal fatty acid's downregulatory actions may also synergistically interact with oncogenic signals to constitutively maintain an elevated FAS-dependent de novo endogenous fatty acid biogenesis in cancer cells in spite of high levels of circulating dietary fatty acids.
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PMID:Why does tumor-associated fatty acid synthase (oncogenic antigen-519) ignore dietary fatty acids? 1560 69

Trastuzumab (Herceptin) is a humanized antibody directed against the extracellular domain of the tyrosine kinase orphan receptor Her-2/neu (erbB-2) that has shown therapeutic efficacy against Her-2/neu-overexpressing breast tumors. However, less than 35% of patients with Her-2/neu-overexpressing metastatic breast cancer respond to trastuzumab as a single agent, whereas the remaining cases do not demonstrate tumor regression. Furthermore, the majority of patients who achieve an initial response generally acquire resistance within one year. Therefore, the identification of the potential mechanisms of resistance to trastuzumab can be very helpful for the development of new compounds, which might overcome that resistance and/or have additive/synergistic antitumor effect when given in association with trastuzumab. Recent studies in breast cancer cells have revealed a bi-directional connection between Her-2/neu and fatty acid synthase (FAS), a major lipogenic enzyme catalyzing the synthesis of long-chain saturated fatty acids from the 2-carbon donors malonyl-CoA and acetyl-CoA. Her-2/neu overexpression stimulates the FAS promoter and ultimately mediates increased endogenous fatty synthesis, and this Her-2/neu-mediated induction of breast cancer-associated FAS is inhibitable by trastuzumab. On the other hand, chemical FAS inhibitors as well as RNA interference-mediated silencing of FAS gene repress Her-2/neu gene expression at the transcriptional level. Moreover, specific FAS blockade synergistically sensitizes breast cancer cells carrying Her-2/neu-oncogene amplification and/or overexpression to trastuzumab-induced cell growth inhibition and apoptotic cell death. Strikingly, FAS inhibition synergistically interacts with trastuzumab in Her-2/neu-negative breast cancer cells engineered to overexpress Her-2/neu, thus suggesting that the molecular linkage between FAS activity and functioning of Her-2/neu cannot be explained only on the basis of a transcriptional repression of Her-2/neu gene promoter. Interestingly, while in liver and adipose tissue FAS produces fat from excess carbon consumed as carbohydrates, which is ultimately stored as triglycerides, in epithelial cancer cells, FAS activity is mainly involved in the production of phospholipids partitioning into detergent-resistant membrane microdomains (lipid raft-aggregates), which point to an active role of FAS in the deregulation of membrane functioning in tumor cells. Importantly, clusters of Her-2/neu and EGFR (erbB-1) co-localize with lipid rafts and the lipid environment in the cell membrane of breast cancer cells profoundly influences their association properties and biological functions. We hypothesize that pharmacological or small interference RNA-induced inhibition of breast cancer-associated FAS will result in major changes in the synthesis of phospholipids which, in turn, should impair a correct cellular localization of Her-2/neu at the cellular membrane of breast cancer cells. In this working model, FAS inhibition could induce a shift in the equilibrium between transport of Her-2/neu to and from the membrane favoring an increased Her-2/neu internalization followed by intracellular degradation, thus enhancing the mechanism of action of the anti-Her-2/neu antibody trastuzumab. Moreover, the inhibition of FAS-driven lipid rafts will also negatively affect EGFR-Her-2/neu cross-talk, an important mechanism of trastuzumab resistance. In summary, the specific blockade of a novel molecular linkage between FAS-regulated membrane composition and functioning of transmembrane growth factor receptors EGFR and Her-2/neu may represent a previously unrecognized therapeutic approach circumventing trastuzumab resistance in breast carcinomas.
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PMID:Targeting fatty acid synthase-driven lipid rafts: a novel strategy to overcome trastuzumab resistance in breast cancer cells. 1578 Apr 99

Among the health-promoting effects of tea and tea polyphenols, the cancer-chemopreventive effects in various animal model systems have been intensively investigated; meanwhile, the hypolipidemic and antiobesity effects in animals and humans have also become a hot issue for molecular nutrition and food research. It has been demonstrated that the body weights of rats and their plasma triglyceride, cholesterol, and LDL-cholesterol have been significantly reduced by feedings of oolong, black, pu-erh, and green tea leaves to the animals. It has been suggested that the inhibition of growth and suppression of lipogenesis in MCF-7 breast cancer cells may be through down-regulation of fatty acid synthase gene expression in the nucleus and stimulation of cell energy expenditure in the mitochondria. The experimental data indicated that the molecular mechanisms of fatty acid synthase gene suppression by tea polyphenols (EGCG, theaflavins) may invite down-regulation of EGFR/PI3K/Akt/Sp-1 signal transduction pathways.
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PMID:Mechanisms of hypolipidemic and anti-obesity effects of tea and tea polyphenols. 1640 8

Cancer cells frequently exhibit a significant increase in overexpression and activity of fatty acid synthase (FASN). Elevated FASN pathway activity also occurs in prostate cancer, the second leading cause of cancer-related death in men in the United States. Studies show that genes associated with an increase in protein expression, such as HER2/neu in breast cancer, are associated with an increase in gene copy number as well as an increase in transcription. In the present study, we evaluated whether FASN follows a similar paradigm in prostate cancer. To date, elevated FASN expression in prostate cancer has not been correlated with gene copy number alterations. Using immunohistochemistry and fluorescence in situ hybridization analysis in paraffin-embedded tissue microarrays, we observed gene copy gain in 24% of all prostate adenocarcinoma specimens examined with concurrent increased FASN protein expression. Immunohistochemistry alone showed 59% of prostate cancer specimens in the same tissue microarray with high FASN expression. Increased FASN gene was observed in 53% of all prostate tissues expressing elevated FASN protein levels and in 2 of 5 prostate tumor cell lines tested. These findings suggest that FASN gene copy number increases may be involved in the resultant increase in FASN protein expression observed in prostatic disease.
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PMID:Fatty acid synthase gene overexpression and copy number gain in prostate adenocarcinoma. 1656 13

Orlistat, an antiobesity drug, is cytostatic and cytotoxic to tumor cells. The antitumor activity of orlistat can be attributed to its ability to inhibit the thioesterase domain of fatty acid synthase (FAS). The objective of the present study was to test the effect of orlistat on endothelial cell proliferation and angiogenesis. Orlistat inhibits endothelial cell FAS, blocks the synthesis of fatty acids, and prevents endothelial cell proliferation. More significantly, orlistat inhibits human neovascularization in an ex vivo assay, which suggests that it may be useful as an antiangiogenic drug. The mechanism of these effects can be traced to the fact that orlistat prevents the display of the vascular endothelial growth factor (VEGF) receptor (VEGFR2/KDR/Flk1) on the endothelial cell surface. Thus, orlistat is an antiangiogenic agent with a novel mechanism of action.
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PMID:Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor. 1701 55

Tumor-associated fatty acid synthase (FAS) is implicated in tumorigenesis and connected to HER2 (human epidermal growth factor receptor 2) by systemic analyses. Suppression of FAS in cancer cells may lead to growth inhibition and cell apoptosis. Our previous study demonstrated that (-)-epigallocatechin 3-gallate (EGCG), the green tea catechin, could down-regulate FAS expression by suppressing EGFR (epidermal growth factor receptor) signaling and downstream phosphatidylinositol 3-kinase (PI3K)/Akt activation in the MCF-7 breast cancer cell line. Herein, we examined the effects of EGCG on FAS expression modulated by another member of the erbB family, that is, HER2 or HER3. We identified that heregulin-beta1 (HRG-beta1), a HER3 ligand, stimulated dose-dependent FAS expression in breast cancer cell lines MCF-7 and AU565, but not MDA-MB-453. The time-dependent increase in FAS expression after HRG-beta1 stimulation was also observed in MCF-7 cells, and this up-regulation was de novo RNA synthesis dependent. Treatment of MCF-7 cells with EGCG markedly inhibited HRG-beta1-dependent induction of mRNA and protein of FAS. EGCG also decreased the phosphorylation of Akt and extracellular signal-regulated kinase 1/2 that were demonstrated as selected downstream HRG-beta1-responsive kinases required for FAS expression using dominant-negative Akt, PI3K inhibitors (LY294002 and wortmannin), or MEK inhibitor (PD98059). FAS induction by HRG-beta1 was also blocked by AG825, a selective HER2 inhibitor, and by genistein, a selective tyrosine kinase inhibitor, indicating the formation of a heterodimer between HER2 and HER3, and their tyrosine kinase activities are essential for HRG-beta1-mediated elevation of FAS. Additionally, growth inhibition of HRG-beta1-treated cells was parallel to suppression of FAS by EGCG. Taken together, these findings extend our previous study to indicate that EGCG may be useful in the chemoprevention of breast carcinoma in which FAS overexpression results from HER2 or/and HER3 signaling.
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PMID:Tea polyphenol (-)-epigallocatechin 3-gallate suppresses heregulin-beta1-induced fatty acid synthase expression in human breast cancer cells by inhibiting phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase cascade signaling. 1753 58


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