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)

Endothelial nitric-oxide synthase (eNOS) plays a crucial role in the regulation of a variety of cardiovascular and pulmonary functions in both normal and pathological conditions. Multiple signaling inputs, including calcium, caveolin-1, phosphorylation by several kinases, and binding to the 90-kDa heat shock protein (Hsp90), regulate eNOS activity. Here, we report a novel mechanism of G protein-dependent regulation of eNOS. We demonstrate that in mammalian cells, the alpha subunit of heterotrimeric G12 protein (G alpha12) can form a complex with eNOS in an activation- and Hsp90-independent manner. Our data show that G alpha12 does not affect eNOS-specific activity, but it strongly enhances total eNOS activity by increasing cellular levels of eNOS. Experiments using inhibition of protein or mRNA synthesis show that G alpha12 increases the expression of eNOS by increasing half-life of both eNOS protein and eNOS mRNA. Small interfering RNA-mediated depletion of endogenous G alpha12 decreases eNOS levels. A quantitative correlation can be detected between the extent of down-regulation of G alpha12 and eNOS in endothelial cells after prolonged treatment with thrombin. G protein-dependent increase of eNOS expression represents a novel mechanism by which heterotrimeric G proteins can regulate the activity of downstream signaling molecules.
Mol Pharmacol 2006 Mar
PMID:Novel mechanisms of G protein-dependent regulation of endothelial nitric-oxide synthase. 1637 62

Tumor suppressor genes play a prominent role in the modification and progression of urinary bladder carcinogenesis as a result of classic genetic alterations. Little is known about the potential significance of epigenetic events, mediated by DNA hypermethylation. This prompted our investigation to explore the global Alu methylation and the promoter methylation of the novel putative tumor suppressor genes caveolin-1 and hDAB2IP, and of p53 in transitional cell carcinomas (TCC), squamous cell carcinomas and undifferentiated small cell carcinomas of the urinary bladder. Quantitative GeneScan analysis revealed that the various histopathological tumor entities showed considerable interindividual variations in the global methylation, but the overall rate did not significantly differ between the various cancer subtypes. With methylation-specific PCR, a high frequency of methylation of the promoter region of the caveolin-1 gene was detected in undifferentiated small cell carcinomas (50%) and in squamous cell carcinomas (25.9%), while TCC were found not to be methylated. By immunohistochemistry, all squamous cell carcinomas showed a strong diffuse overexpression of caveolin-1, whereas undifferentiated small cell cancers lacked any expression. High-grade, high-stage TCC disclosed a higher incidence (60%) and a substantially stronger expression than low-grade, low-stage TCC (42.9%). Our findings suggest that hypermethylation of the caveolin-1 gene and an abnormal protein expression play a crucial role in cell differentiation, and in the phenotypical conversion of TCC into nonurothelial carcinomas. Promoter methylation of the hDAB2IP gene occurred more frequently in advanced muscle invasive (72.7%) than in superficial noninvasive (50%) TCC. DNA hypermethylation of p53 was detected in a quarter of the low-grade, low-stage TCC and undifferentiated small cell carcinomas, but only sporadically in squamous cell carcinomas, and was absent in high-grade, high-stage TCC. In conclusion, aberrant methylation and abnormal protein expression of the caveolin-1-gene is involved in the formation of nonurothelial carcinomas of the urinary bladder and promoter methylation of the hDAB2IP gene in the progression of TCC from a low to a high malignant potential.
Int J Mol Med 2006 Jan
PMID:Transitional cell carcinomas and nonurothelial carcinomas of the urinary bladder differ in the promoter methylation status of the caveolin-1, hDAB2IP and p53 genes, but not in the global methylation of Alu elements. 1632 5

The expression of 76 sequences, previously isolated as differentially expressed in visceral white adipose tissue (WAT) of female rats, fed with a high-fat diet for 11 days (Lopez et al., Biochem Biophys Res Comm 318: 234-239, 2004), was analyzed in epidydimal WAT of male rats after a feeding period of 65 days with the same diet, using microarray technology. After Northern blot validation of the results, only three genes appeared upregulated (caveolin-2, the alpha-1 chain of haemoglobin and rat mammary tumor-7) and two downregulated (adiponectin and dystroglycan). We have also analyzed caveolin-1 gene expression and found that follows the opposite pattern of caveolin-2, indicating that they are inversely regulated. Our results suggest that if feeding with a high-fat diet is prolonged, many of the initial changes in gene expression, probably aimed to consume the energy surplus and prevent excessive fat deposition, are not maintained, and adaptation to an increased lipid storage is developed.
Mol Cell Biochem 2005 Jul
PMID:High-fat feeding period affects gene expression in rat white adipose tissue. 1633 90

Nitric oxide plays a crucial role in myocardial ischemia reperfusion injury as well as in myocardial adaptation to ischemic stress. To understand the dichotomy of nitric oxide behavior in the ischemic myocardium, isolated rat hearts were subjected to ischemia/reperfusion protocol. The tissue contents of sphingomyelin (SM), ceramide and sphingosine were determined by high performance thin layer chromatography (HPTLC). The myocardial plasma proteins were immunoprecipitated with caveolin-1 specific antibody. Ischemia/reperfusion resulted in the breakdown of SM with corresponding accumulation of ceramide and sphingosine. Immunoprecipitation with eNOS-specific antibody revealed the association of eNOS with caveolin-1 fraction of the heart. Ischemia/reperfusion caused a depression of contractile function and an increased apoptotic cell death and myocardial infarct size, which were reversed by pre-perfusing the hearts with desipramine, an sphingomyelinase inhibitor that also prevented ceramide accumulation and eNOS association with caveolin-1. The similar results were obtained when the hearts were adapted to ischemic stress by subjecting them to repeated reversible ischemia and reperfusion. The results indicate that ischemia/reperfusion causes an increase in eNOS, which is unavailable to the ischemic heart because of its binding with caveolin-1. Ceramide plays a crucial role in this process, because prevention of ceramide formation either by myocardial adaptation to ischemia or with desipramine results in the inhibition of eNOS association with caveolin-1 thereby reducing myocardial ischemic reperfusion injury.
J Mol Cell Cardiol 2006 Feb
PMID:Role of lipid rafts in ceramide and nitric oxide signaling in the ischemic and preconditioned hearts. 1633 60

This immunocytochemical study revealed the expression of caveolin-1, a major protein of caveolae, in the rat temporomandibular joint. In the synovial lining layer, immunoreactive products for caveolin-1 were detected on the cell membrane of the fibroblast-like type B cells, as confirmed by immunocytochemistry for heat shock protein 25. The cells in the articular disk, the articular layer, and zone of proliferation of the mandibular condyle also showed intense immunoreactions for caveolin-1.
Anat Rec A Discov Mol Cell Evol Biol 2006 Jan
PMID:Expression of caveolin-1 in the rat temporomandibular joint. 1634 13

Caveolin-1 has been reported to regulate apoptosis, lipid metabolism, and endocytosis in macrophages. In the present study, we demonstrate that caveolin-1 can act as a potent immunomodulatory molecule. We first observed caveolin-1 expression in murine alveolar macrophages by Western blotting and immunofluorescence microscopy. Loss-of-function experiments using small interfering RNA showed that down regulating caveolin-1 expression in murine alveolar and peritoneal macrophages increased LPS-induced proinflammatory cytokine TNF-alpha and IL-6 production but decreased anti-inflammatory cytokine IL-10 production. Gain-of-function experiments demonstrated that overexpression of caveolin-1 in RAW264.7 cells decreased LPS-induced TNF-alpha and IL-6 production and augmented IL-10 production. p38 mitogen-activated protein kinase (MAPK) phosphorylation was increased by overexpressing caveolin-1 in RAW264.7 cells, whereas c-Jun N-terminal kinase, extracellular signal-regulated kinase MAPK, and Akt phosphorylation were inhibited. The antiinflammatory modulation of LPS-induced cytokine production by caveolin-1 was significantly abrogated by the administration of p38 inhibitor SB203580 in RAW264.7 cells. Peritoneal macrophages isolated from MKK3 null mice did not demonstrate any modulation of LPS-induced cytokine production by caveolin-1. LPS-induced activation of NF-kappaB and AP-1 determined by electrophoretic mobility shift assay were significantly reduced by overexpressing caveolin-1 in RAW264.7 cells. The reductions were attenuated by the administration of p38 inhibitor SB203580. Taken together, our data suggest that caveolin-1 acts as a potent immunomodulatory effector molecule in immune cells and that the regulation of LPS-induced cytokine production by caveolin-1 involves the MKK3/p38 MAPK pathway.
Am J Respir Cell Mol Biol 2006 Apr
PMID:Caveolin-1 confers antiinflammatory effects in murine macrophages via the MKK3/p38 MAPK pathway. 1635 62

Recently, it has been shown that 17beta estradiol (E2) induces a rapid and transient activation of the Src ERK phosphorylation cascade: a clear indication that the alpha oestrogen receptor (ERalpha) is able to associate with the plasma membrane. Increasing evidence suggests that caveolae, which are caveolin-1 containing, highly hydrophobic membrane domains, play an important role in E2 induced signal transduction. Caveolae can accumulate signalling molecules preferentially; thus, they may have a regulatory role in signalling processes. Results from previous experiments have shown that E2 treatment decreased the number of surface connected caveolae significantly in uterine smooth muscle cells and also downregulated the expression of caveolin-1. In addition to providing further evidence that ERalpha interacts with caveolin/caveolae in uterine smooth muscle cells, this study also shows that the interaction between caveolin-1 and ERalpha is actually facilitated by E2. One of the signal transduction components found to accumulate in caveolae is Src kinase in an amount that increases simultaneously with increases in the amount of ERalpha. Upon E2 treatment, Src kinase is tyrosine phosphorylated, which, in turn, stimulates Src kinase to phosphorylate caveolin-1. Phosphorylation of caveolin-1 can drive caveolae to pinch off from the plasma membrane, thereby decreasing the amount of plasma membrane-associated caveolin-1. This loss of caveolin/caveolae activates the signal cascade that triggers cell proliferation.
Mol Cell Endocrinol 2005 Dec 21
PMID:Oestrogen-mediated tyrosine phosphorylation of caveolin-1 and its effect on the oestrogen receptor localisation: an in vivo study. 1636 81

Monocrotaline (MCT) causes pulmonary hypertension in the rat by a mechanism characterized by megalocytosis (enlarged cells with enlarged endoplasmic reticulum and Golgi and a cell cycle arrest) of pulmonary arterial endothelial (PAEC), arterial smooth muscle, and type II alveolar epithelial cells. In cell culture, although megalocytosis is associated with a block in entry into mitosis in both lung endothelial and epithelial cells, DNA synthesis is stimulated in endothelial but inhibited in epithelial cells. The molecular mechanism(s) for this dichotomy are unclear. While MCTP-treated PAEC and lung epithelial (A549) cells both showed an increase in the "promitogenic" transcription factor STAT3 levels and in the IL-6-induced nuclear pool of PY-STAT3, this was transcriptionally inactive in A549 but not in PAEC cells. This lack of transcriptional activity of STAT3 in A549 cells correlated with the cytoplasmic sequestration of the STAT3 coactivators CBP/p300 and SRC1/NcoA in A549 cells but not in PAEC. Both cell types displayed a Golgi trafficking block, loss of caveolin-1 rafts, and increased nuclear Ire1alpha, but an incomplete unfolded protein response (UPR) with little change in levels of UPR-induced chaperones including GRP78/BiP. There were discordant alterations in cell cycle regulatory proteins in the two cell types such as increase in levels of both cyclin D1 and p21 simultaneously, but with a decrease in cdc2/cdk1, a kinase required for entry into mitosis. While both cell types showed increased cytoplasmic geminin, the DNA synthesis-initiating protein Cdt1 was predominantly nuclear in PAEC but remained cytoplasmic in A549 cells, consistent with the stimulation of DNA synthesis in the former but an inhibition in the latter cell type. Thus differences in cell type-specific alterations in subcellular trafficking of critical regulatory molecules (such as CBP/p300, SRC1/NcoA, Cdt1) likely account for the dichotomy of the effects of MCTP on DNA synthesis in endothelial and epithelial cells.
Am J Physiol Lung Cell Mol Physiol 2006 Jun
PMID:Discordant regulatory changes in monocrotaline-induced megalocytosis of lung arterial endothelial and alveolar epithelial cells. 1641 77

Long-term opioid agonist treatment results in adenylyl cyclase superactivation. A recent "RAVE" theory implicates a direct correlation between the ability of agonist to induce receptor internalization and the magnitude of adenylyl cyclase superactivation. We decided to test such a theory by examining the adenylyl cyclase superactivation after long-term activation of mu-opioid receptor (MOR) in an EcR293 cell model. We examined the magnitudes of adenylyl cyclase superactivation in the presence of naloxone after long-term treatment with morphine, etorphine, and methadone, three agonists reported to have differential activities in promoting MOR internalization. It can be shown that the magnitudes of adenylyl cyclase superactivation after treating with these three agonists, although different, were dependent on MOR density. Blunting MOR internalization with the dominant-negative mutant of dynamin, K44E, did not alter the magnitude of either morphine- or etorphine-induced adenylyl cyclase superactivation. In the presence of diprenorphine, the magnitude of adenylyl cyclase superactivation after etorphine treatment was identical to that observed with morphine. It could be demonstrated further that adenylyl cyclase superactivation is dependent on the cell surface-located MOR. Sucrose gradient fractionation demonstrated the colocalization of MOR and adenylyl cyclase V/VI with caveolin-1, a marker for lipid rafts. After long-term agonist treatment, the majority of MOR remained at the lipid rafts. Methyl-beta-cyclodextrin (MbetaCD) completely blunted the adenylyl cyclase superactivation and agonist-induced receptor internalization. These MbetaCD actions were reversed by incubating the cells with cholesterol. Thus, the adenylyl cyclase superactivation is not dependent on agonist-induced receptor internalization. Rather, the location of MOR at lipid rafts is an absolute requirement for the observed adenylyl cyclase superactivation.
Mol Pharmacol 2006 Apr
PMID:Adenylyl cyclase superactivation induced by long-term treatment with opioid agonist is dependent on receptor localized within lipid rafts and is independent of receptor internalization. 1641 76

CD99 was recently reported to be under control of the osteoblast-specific transcription factor Cbfa1 (RUNX2) in osteoblasts, suggesting a role in the phato-physiology of these cells. No extensive information is available on the role(s) of this molecule in malignant phenotype, and osteosarcoma, in particular, has never been studied. We report that in 11 different cell lines and 17 clinical samples CD99 expression is either undetectable or very low. Being expressed in the normal counterpart, we tested the hypothesis that CD99 down-regulation may have a role in osteosarcoma development and progression. CD99-forced expression in two osteosarcoma cell lines significantly reduced resistance to anoikis, inhibited growth in anchorage independence as well as cell migration, and led to abrogation of tumorigenic and metastatic ability. Therefore, the molecule acts as a potent suppressor of malignancy in osteosarcoma. CD99 gene transfection induces caveolin-1 up-regulation and the two molecules were found to colocalize on the cell surface. Treatment with antisense oligonucleotides to caveolin-1 abrogates the effects of CD99 on migration. The findings point to an antioncogenic role for CD99 in osteosarcoma, likely through the regulation of caveolin-1 and inhibition of c-Src kinase activity.
Mol Biol Cell 2006 Apr
PMID:CD99 acts as an oncosuppressor in osteosarcoma. 1642 Dec 47


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