Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Previous reports have indicated that, in vivo, the serotonin-2 (5-HT2) receptor is responsive to exogenously administered glucocorticoids. The ability of the glucocorticoid receptor (GR) to influence transcription of the rat 5-HT2 receptor gene was tested in two different experimental paradigms. In both sets of experiments transcription of the 5-HT2 gene was monitored with a promoter-reporter plasmid in which the promoter for the 5-HT2 gene was driving the expression of the firefly luciferase gene. In the first, the 5-HT2 promoter-reporter plasmid was transfected directly into RS1 cells followed by dexamethasone treatment. In the second set of experiments, the cDNA encoding the GR carried on a separate expression vector was cotransfected into CCL-39 or Neuro-2a cells along with the 5-HT2 promoter-reporter plasmid. These cells were then exposed to dexamethasone. In the RS-1 and CCL-39 transfection experiments, the dexamethasone treatment caused an inhibition of transcription of the 5-HT2 promoter, whereas in the Neuro-2a cells, the dexamethasone treatment stimulated transcription from the 5-HT2 promoter. These responses were dependent on the presence of the GR. The effect of the activated GR would seem to be indirect as sequence analysis of the 4.2 kb preceding the site of transcription initiation revealed only an 11/15 nt match to a putative glucocorticoid response element (GRE), and deletion of this sequence did not alter the response to dexamethasone. Sequence analysis revealed a variety of potential response elements for other known transcription factors, including four potential AP-1 response elements.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1995 Jul
PMID:Transcriptional control of the rat serotonin-2 receptor gene. 747 30

We previously showed that thrombin-stimulated DNA synthesis in CCL 39 cells was inhibited by hydroxyurea (HU) and bathophenanthroline disulfonate (BPS) (Proc. Natl. Acad. Sci. USA, in press). A clear difference exists between these two inhibitors. Inhibition mediated by HU was immediate and must be present in the culture medium. BPS was equally effective when it was present in the medium or after preincubation, but it required at least 12 h to achieve maximal effect. The permeable form 1,10 phenanthroline had the same inhibitory effect in short-term incubations that BPS. Moreover, 1,10 phenanthroline was cytotoxic in long-term incubations indicating that the site of BPS inhibition was outside the cell. Further, long-term incubations with HU did not affect the ability of the cell to reinitiate DNA synthesis after removal of the chelator.
Biochem Mol Biol Int 1994 Sep
PMID:Iron chelators hydroxyurea and bathophenanthroline disulfonate inhibit DNA synthesis by different pathways. 784 37

Glycosylphosphatidylinositol (GPI) was previously identified in rabbit articular chondrocytes as being a precursor of inositolphosphate glycan (IPG), released upon (Transforming Growth Factor-beta) (TGF-beta) exposure, and capable of mimicking the proliferative effects of the growth factor. Here, using mink lung epithelial cells (CCL 64), which are known to be growth-inhibited by TGF-beta, we studied the potential role of GPI-derived molecules in the antiproliferative effect of TGF-beta1. We first identified an endogenous pool of GPI material and three different anionic forms of IPG in epithelial cells pre-labeled with [3H]glucosamine. Shortly (8 min) after TGF-beta1 addition, the cells responded by a rapid and transient hydrolysis of GPI, accompanied by the release of the most anionic form of IPG. This TGF-beta-released IPG, after partial purification, was shown to decrease the proliferation of CCL 64 cells. Moreover, anti-IPG antibodies reduced the effects of TGF-beta and blocked the effects of partially purified IPG. These data strongly suggest that GPI hydrolysis may be an early step of the TGF-beta signalling pathway involved in growth inhibition of epithelial cells.
Mol Cell Biochem 2000 May
PMID:Glycosylphosphatidylinositol (GPI) hydrolysis by transforming growth factor-beta1 (TGF-beta1) as a potential early step in the inhibition of epithelial cell proliferation. 1093 38

The underlying cause of the selective death of the nigral dopaminergic neurons in Parkinson's disease is not fully understood. Tetrahydrobiopterin (BH4) is synthesized exclusively in the monoaminergic, including dopaminergic, cells and serves as an endogenous and obligatory cofactor for syntheses of dopamine and nitric oxide. Because BH4 contributes to the syntheses of these two potential oxidative stressors and also undergoes autoxidation, thereby producing reactive oxygen species, it was possible that BH4 may play a role in the selective vulnerability of dopaminergic cells. BH4 given extracellularly was cytotoxic to catecholamine cells CATH. a, SK-N-BE(2)C, and PC12, but not to noncatecholamine cells RBL-2H3, CCL-64, UMR-106-01, or TGW-nu-1. This was not caused by increased dopamine or nitric oxide, because inhibition of their syntheses did not attenuate the damage and BH4 did not raise their cellular levels. Dihydrobiopterin and biopterin were not toxic, indicating that the fully reduced form is responsible. The toxicity was caused by generation of reactive oxygen species, because catalase, superoxide dismutase, and peroxidase protected the cells from the BH4-induced demise. Furthermore, thiol agents, such as reduced glutathione, dithiothreitol, beta-mercaptoethanol, and N-acetylcysteine were highly protective. The BH4 toxicity was initiated extracellularly, because elevation of intracellular BH4 by sepiapterin did not result in cell damage. BH4 was spontaneously released from the cells of its synthesis to a large extent, and the release was not further enhanced by calcium influx. This BH4-induced cytotoxicity may represent a mechanism by which selective degeneration of dopaminergic terminals and neurons occur.
Mol Pharmacol 2000 Sep
PMID:Tetrahydrobiopterin is released from and causes preferential death of catecholaminergic cells by oxidative stress. 1095 58

Transforming growth factor beta1 (TGF-beta1), a multifunctional cytokine participates in the proliferation and differentiation of various cell types. Platelets are an important source of TGF-beta1 and are physiologically linked to a variety of chronic illnesses including cancer, heart disease and inflammation. It is well known that dietary lipids modulate platelet function. Whether dietary lipids affect growth factor status of platelets is not known. This study addresses the effect of dietary lipids on TGF-beta1 status of the platelets. Male 8 month-old Sprague Dawley rats were allocated to different diet groups. The high fat diets ( 18% by weight) comprising of high fat beef tallow (HFB), high fat corn oil (HFC), high fat fish oil (HFF) and high fat olive oil (HFO) and one low fat diet containing low fat soybean oil (LFS) (5% by weight) were fed to the experimental animals for 6 weeks. The TGF-beta1 status in the platelet lysate was assessed by using the CCL-64 mink lung cell bioassay and by Western blot analysis. Platelet lysates were evaluated for their ability to inhibit the growth of the CCL-64 mink lung cells, unexpectedly platelet lysates stimulated growth. The stimulatory effect of platelet lysate was in the order HFF > HFO > HFB > HFC > LFS. Acidification of the lysates to activate the latent form of TGF-beta1 resulted in the loss of the growth stimulatory potential of the platelet lysates in all the groups. Western blot analysis of the platelet lysates to detect the level of TGF-beta1 protein demonstrated that HFB diet group had the highest level of TGF-beta1 and the HFC diet group had the lowest level of TGF-beta1 and were significantly different (p < 0.05) as compared to the other three diet groups. These findings demonstrate that dietary lipids varying in their fatty acid composition, profoundly affect the level of growth modulating constituents of the platelets. Further studies are warranted to refine our understanding of the effect of dietary constituents on the physiology of the platelets.
Mol Cell Biochem 2000 Aug
PMID:Evidence for the involvement of dietary lipids on the modulation of transforming growth factor-beta1 in the platelets of male rats. 1105 57

Potent photosensitizer Hypericin (HY), is a lipid soluble perylquinone derivative of the genus Hypericum and has a strong photodynamic effect on tumors and viruses. However, the mechanisms of tumor cell death induced by this compound is still unclear. Furthermore, there are no reports on mechanisms in cell apoptosis induced by perylquinones in human nasopharyngeal carcinoma (NPC) and other mucosal cells. We studied the photodynamic effects of HY compound in poorly differentiated (CNE2) and moderately differentiated (TW0-1) human NPC cells as well as human mucosal colon (CCL-220.1) and bladder (SD) cells. Using these cell lines we investigated few hall marks of apoptotic commitments in a drug and light dose dependent manner. Tumor cells photoactivated with HY showed cell size shrinkage and an increase in the sub-diploid DNA content. A loss of membrane phospholipid asymmetry associated with apoptosis was induced in all tumor cell lines as evidenced by the externalization of phosphatidylserine. Under apoptotic conditions, Western blot analysis of poly (ADP-ribose) polymerase, a caspase substrate, showed the classical cleavage pattern (116-85 kDa) associated with apoptosis in PDT-treated cell lysates. In addition, 85 kDa cleaved product was blocked by using tetrapeptide caspase inhibitors such as DEVD-CHO or z-VAD-fmk. These results demonstrate that tumor cell death induced by photoactivated HY is mediated by caspase proteases. This study also identifies that CNE2, CCL-220.1 (colon) and SD (bladder) cell lines are more sensitive than TW0-1 cell line to PDT using perylquinone HY.
Int J Mol Med 2001 Nov
PMID:Induction of apoptosis by Hypericin through activation of caspase-3 in human carcinoma cells. 1160 21

Nasopharyngeal carcinoma (NPC) is a malignant disease of the head/neck region with a 5-year survival level of approximately 65%. To explore the novel therapeutic strategies in the management of this disease, the potential effects of photodynamic therapy (PDT) in NPC cells were investigated. PDT, a new mode of treatment, is based on the combined use of light-absorbing compounds and light irradiation. Two human NPC cells such as, poorly differentiated (NPC/CNE2) and moderately differentiated (NPC/TW0-1) and other types of tumor cells like colon (CCL-220.1) and bladder (SD) undergo rapid apoptosis when treated with PDT sensitized with hypericin (HY). It has been shown that this compound has a strong photodynamic effect on tumors and viruses. However, the initiating events of PDT sensitized HY-induced apoptosis are not identified completely. In this study, we sought to determine whether Fas/FasL upregulation and involvement of mitochondrial events are an early event in HY-treated PDT induced apoptosis. Loss of mitochondrial transmembrane potential, release of cytochrome c, involvement of caspases 8 and 3 and the status caspase-3 specific substrate PARP, were evaluated in PDT treated tumor cells. Photosensitization of HY enhanced both CD95/CD95L expression and induced CD95-signaling dependent cell death in all tumor cell lines studied. CD95/CD95L expression appeared within 2 h following light irradiation and appeared to be a principal event in PDT induced apoptosis. Furthermore, these results indicate that release of mitochondrial cytochrome c into the cytoplasm within 2-3 h post PDT is a secondary event following the activation of initiator caspase-8 preceding Apaf-1, caspase-9 and caspase-3 activation, cleavage of PARP and DNA fragmentation.
Int J Mol Med 2002 Jun
PMID:Hypericin induced death receptor-mediated apoptosis in photoactivated tumor cells. 1201 77

Type-1 and type-2 lung granulomas, respectively, elicited by bead immobilized Mycobacteria bovis and Schistosoma mansoni egg antigens (Ags) display different patterns of chemokine expression. This study tested the hypothesis that chemokine expression patterns were related to upstream cytokine signaling. Using quantitative transcript analysis, we defined expression profiles for 16 chemokines and then examined the in vivo effects of neutralizing antibodies against interferon-gamma (IFN-gamma), interleukin (IL)-4, IL-10, IL-12, and IL-13. Transcripts for CXCL2, -5, -9, -10, and -11 and the CCL chemokine, CCL3, and lymphotactin (XCL1), were largely enhanced by Th1-related cytokines, IFN-gamma or IL-12. Transcripts for CCL11, CCL22, CCL17, and CCL1 were enhanced largely by Th2-related cytokines, IL-4, IL-10, or IL-13. Transcripts for CCL4, CCL2, CCL8, CCL7, and CCL12 were potentially induced by either Th1- or Th2-related cytokines, although some of these showed biased expression. IFN-gamma and IL-4 enhanced the greatest complement of transcripts, and their neutralization had the greatest anti-inflammatory effect on type-1 and type-2 granulomas, respectively. Th1/Th2 cross-regulation was evident because endogenous Th2 cytokines inhibited type-1, whereas Th1 cytokines inhibited type-2 biased chemokines. These findings reveal a complex cytokine-chemokine regulatory network that dictates profiles of local chemokine expression during T cell-mediated granuloma formation.
Am J Respir Cell Mol Biol 2003 Jul
PMID:Cytokine-chemokine networks in experimental mycobacterial and schistosomal pulmonary granuloma formation. 1260 Aug 21

Previous studies of human hepatitis B virus (HBV) transcription revealed the requirement of two enhancer elements. Enhancer I (EnhI) is located upstream of the X promoter and is targeted by multiple activators, including basic leucine zipper proteins, and enhancer II (EnhII) is located upstream to the PreCore promoter and is targeted mainly by nuclear receptors (NRs). The mode of interplay between these enhancers and their unique contributions in regulating HBV transcription remained obscure. By using time course analysis we revealed that the HBV transcripts are categorized into early and late groups. Chang (CCL-13) cells are impaired in expression of the late transcripts. This could be corrected by overexpressing EnhII activators, such as hepatocyte nuclear factor 4 alpha, the retinoid X receptor alpha, and the peroxisome proliferator-activated receptor alpha, suggesting that in Chang cells EnhI but not EnhII is active. Replacing the 5'-end EnhI sequence with a synthetic Gal4 response (UAS) DNA fragment ceased the production of the early transcripts. Under this condition NR overexpression poorly activated EnhII. However, activation of the UAS by Gal4-p53 restored both the expression of the early transcripts and the EnhII response to NRs. Thus, a functional EnhI is required for activation of EnhII. We found a major difference between Gal4-p53 and Gal4-VP16 behavior. Gal4-p53 activated the early transcripts, while Gal4-VP16 inhibited the early transcripts but activated the late transcripts. These findings indicate that the composition of the EnhI binding proteins may play a role in early to late switching. Our data provides strong evidence for the role of EnhI in regulating global and temporal HBV gene expression.
Mol Cell Biol 2004 Feb
PMID:Enhancer I predominance in hepatitis B virus gene expression. 1474 94

Acute lung injury is a complex illness with a high mortality rate (>30%) and often requires the use of mechanical ventilatory support for respiratory failure. Mechanical ventilation can lead to clinical deterioration due to augmented lung injury in certain patients, suggesting the potential existence of genetic susceptibility to mechanical stretch (6, 48), the nature of which remains unclear. To identify genes affected by ventilator-induced lung injury (VILI), we utilized a bioinformatic-intense candidate gene approach and examined gene expression profiles from rodent VILI models (mouse and rat) using the oligonucleotide microarray platform. To increase statistical power of gene expression analysis, 2,769 mouse/rat orthologous genes identified on RG_U34A and MG_U74Av2 arrays were simultaneously analyzed by significance analysis of microarrays (SAM). This combined ortholog/SAM approach identified 41 up- and 7 downregulated VILI-related candidate genes, results validated by comparable expression levels obtained by either real-time or relative RT-PCR for 15 randomly selected genes. K-mean clustering of 48 VILI-related genes clustered several well-known VILI-associated genes (IL-6, plasminogen activator inhibitor type 1, CCL-2, cyclooxygenase-2) with a number of stress-related genes (Myc, Cyr61, Socs3). The only unannotated member of this cluster (n = 14) was RIKEN_1300002F13 EST, an ortholog of the stress-related Gene33/Mig-6 gene. The further evaluation of this candidate strongly suggested its involvement in development of VILI. We speculate that the ortholog-SAM approach is a useful, time- and resource-efficient tool for identification of candidate genes in a variety of complex disease models such as VILI.
Am J Physiol Lung Cell Mol Physiol 2005 Sep
PMID:Bioinformatic identification of novel early stress response genes in rodent models of lung injury. 1590 77


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