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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of cannabinoid receptor I (CBR-1) in the induction of decidualization was examined using decidual fibroblasts and human endometrial stromal cells as model systems. Decidual fibroblasts decidualized in vitro for 3 and 6 days in the presence of the CBR-1 agonist R(+)-WIN 55,212-2 mesylate (WIN, 0.1-10 microM) expressed less of the decidualization-specific markers prolactin, CBR-1, forkhead (FKHR), TIMP-3, laminin, endometrial bleeding associated factor (EBAF), decorin and insulin-like growth factor binding protein-1 (IGFBP-1) mRNA levels compared to control cells. The maximal decrease for each transcript was in the range of 50-99%. In contrast, cells exposed to the CBR-1 inhibitor AM-251 (1 microM) expressed about two-fold higher levels of the decidualization-specific marker gene mRNAs. The WIN-exposed cells showed a marked decrease in intracellular cAMP levels and a progressive, concentration-dependent increase in DNA fragmentation (TUNEL assay) and caspase 3 levels during decidualization compared to control cells. These studies strongly suggest that activation of CBR-1 inhibits human decidualization and stimulates apoptosis by a cAMP-dependent mechanism.
Mol Cell Endocrinol 2005 Jan 14
PMID:Cannabinoid receptor I activation markedly inhibits human decidualization. 1560 30

beta-Adrenoceptor agonists reportedly decrease spontaneous apoptosis of peripheral blood eosinophils; however, its signaling pathway is unknown. Survival signals can be elicited by the activation of phosphatidylinositol 3-kinase (PI3K) and Akt, both of which are known to be potent regulators of apoptosis, and Akt in turn inactivates Forkhead transcription factors, including FKHR (Forkhead in rhabdomyosarcoma). We have investigated the effect of beta-agonists on apoptosis of local eosinophils isolated from the airways and the involvement of PI3K, Akt, and FKHR in its survival signal. Eosinophils obtained from immunized mice by bronchoalveolar lavage after allergen provocation underwent apoptosis in a time-dependent manner. Incubation of eosinophils with isoproterenol or formoterol dose-dependently inhibited both spontaneous eosinophil apoptosis and apoptosis induced by Fas receptor activation. Incubation with cAMP or forskolin also inhibited eosinophil apoptosis. The PI3K inhibitors wortmannin and LY-294002 and an Akt inhibitor, 1-L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, but not a mitogen-activated protein kinase kinase inhibitor PD-98059, blocked isoproterenol-mediated eosinophil survival. Wortmannin also inhibited cAMP-mediated eosinophil survival. Isoproterenol rapidly induced phosphorylation of Akt and FKHR in eosinophils in a PI3K-dependent manner. These findings indicate that the PI3K-Akt-FKHR pathway conveys a critical survival signal induced by beta-agonists in airway eosinophils.
Am J Physiol Lung Cell Mol Physiol 2005 May
PMID:Activation of PI3K-Akt pathway mediates antiapoptotic effects of beta-adrenergic agonist in airway eosinophils. 1561 57

Glial cell line-derived neurotrophic factor (GDNF)/Ret signaling is required for enteric neural crest survival, proliferation, migration and process extension, but signaling pathways that mediate enteric nervous system (ENS) precursor development are poorly understood. We therefore examined GDNF effects on immunoselected ENS precursor survival and neuronal process extension in the presence of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathway inhibitors. These studies demonstrated that GDNF promotes ENS precursor survival through phosphatidylinositol-3-kinase. Specifically, GDNF induces phosphorylation of Akt and loss of the Akt substrates FOXO1 and FOXO3a from the nucleus of ENS precursors. Furthermore, dominant negative Akt or active FOXO1 constructs promote ENS precursor cell death while a dominant negative FOXO1 construct prevents cell death. In contrast, the MAPK kinase inhibitor PD98059 did not influence ENS precursor survival or neurite extension. These data demonstrate a critical role for PI-3 kinase/Akt/FOXO signaling, but not for MAPK in ENS precursor survival and neurite extension.
Mol Cell Neurosci 2005 May
PMID:Enteric neuroblasts require the phosphatidylinositol 3-kinase/Akt/Forkhead pathway for GDNF-stimulated survival. 1586 51

Muscle satellite cells are believed to form a stable, self-renewing pool of stem cells in adult muscle where they function in tissue growth and repair. A regulatory disruption of growth and differentiation of these cells is assumed to result in tumor formation. Here we provide for the first time evidence that sonic hedgehog (Shh) regulates the cell fate of adult muscle satellite cells in mammals. Shh promotes cell division of satellite cells (and of the related model C2C12 cells) and prevents their differentiation into multinucleated myotubes. In addition, Shh inhibits caspase-3 activation and apoptosis induced by serum deprivation. These effects of Shh are reversed by simultaneous administration of cyclopamine, a specific inhibitor of the Shh pathway. Taken together, Shh acts as a proliferation and survival factor of satellite cells in the adult muscle. Our results support the hypothesis of the rhabdomyosarcoma origin from satellite cells and suggest a role for Shh in this process.
Cell Mol Life Sci 2005 Aug
PMID:Pleiotropic effects of sonic hedgehog on muscle satellite cells. 1600 93

Glucose-6-phosphatase catalyzes the final step in the gluconeogenic and glycogenolytic pathways. Glucocorticoids stimulate glucose-6-phosphatase catalytic subunit (G6Pase) gene transcription and studies performed in H4IIE hepatoma cells demonstrate the presence of a glucocorticoid response unit (GRU) in the proximal G6Pase promoter. In vitro deoxyribonuclease I footprinting analyses show that the glucocorticoid receptor binds to three glucocorticoid response elements (GREs) in the -231 to -129 promoter region and transfection results indicate all three contribute to glucocorticoid induction of G6Pase gene transcription. Furthermore, binding sites for hepatocyte nuclear factor-1 and -4, CRE binding factors, and FKHR (FOXO1a) are required for the full glucocorticoid response. Chromatin immunoprecipitation assays show that dexamethasone treatment stimulates glucocorticoid receptor and FKHR binding to the endogenous G6Pase promoter. Surprisingly, although glucocorticoids stimulate G6Pase gene transcription, deoxyribonuclease I footprinting and transfection analyses demonstrate the presence of a negative GRE and an associated negative accessory factor element in the -271 to -225 promoter region, which inhibit the glucocorticoid response. This appears to be the first report of a promoter that contains both positive and negative GREs, which function within the same cellular environment. We hypothesize that targeted signaling to the negative accessory element within the GRU may provide tight regulation of the glucocorticoid stimulation.
Mol Endocrinol 2005 Dec
PMID:The glucose-6-phosphatase catalytic subunit gene promoter contains both positive and negative glucocorticoid response elements. 1603 30

Caveolin-3 (Cav-3) is a principal structural protein of caveolae membrane domains. Animal studies have revealed that Cav-3 is expressed in skeletal and cardiac myocytes but absent in other types of cells. Recent studies have shown that abnormalities in the Cav-3 gene are associated with some forms of muscular dystrophy, while skeletal muscle abnormalities have been observed in Cav-3 transgenic and knockout mice. In this study the authors evaluated the distribution of Cav-3 in normal human tissues and compared the expression of Cav-3 with that of myogenin and myoD1 in rhabdomyosarcoma (RMS), malignant mixed mullerian tumor (MMMT), and an array of neoplasms that mimic RMS to assess the utility of Cav-3 as a diagnostic marker for tumors with skeletal muscle differentiation. In nonneoplastic human tissues, crisp membrane staining for Cav-3 was present in cardiac and skeletal myocytes and occasionally in arterial smooth muscle cells and prostatic stromal cells, while other cell types were negative for Cav-3. Eighty-eight percent (21/24) of RMS studied were positive for Cav-3. Positive staining was generally observed in the more maturely differentiated tumor cells but not the primitive tumor cells. Eight of nine cases of MMMT stained strongly with Cav-3 in their rhabdomyosarcomatous component but not in other components. Fifty-four other neoplasms (13 leiomyosarcomas, 8 neuroblastomas, 5 lymphomas, 6 Wilms tumors without skeletal muscle differentiation, 5 Ewing sarcomas, 4 malignant fibrous histiocytomas, 4 angiosarcomas, 6 malignant melanomas, and 3 synovial sarcomas) were negative for Cav-3 expression. Nearly all (96% [23/24]) cases of RMS were positive for myogenin, while 88% (21/24) were positive for myoD1. Primitive tumor cells showed significantly increased expression of myoD1 and myogenin; conversely, more differentiated tumor cells were negative or weakly stained. The rhabdomyosarcomatous component of MMMT stained focally with myogenin and myoD1, in contrast to the strong Cav-3 labeling in these cells. These results demonstrate that Cav-3 is specifically expressed in human cardiac and skeletal myocytes. Furthermore, its high specificity and relatively high sensitivity (88%) for tumors with skeletal muscle differentiation suggest that Cav-3 is a valuable marker for these tumors and may be used to assess the degree of differentiation of RMS and to identify residual tumor cells in post-chemotherapy specimens.
Appl Immunohistochem Mol Morphol 2005 Sep
PMID:Caveolin-3 is a sensitive and specific marker for rhabdomyosarcoma. 1608 47

Menstruation, or cyclic shedding of nonpregnant endometrial tissue with associated bleeding, occurs only in humans and a few other species. This breakdown of the endometrium in response to falling ovarian progesterone levels is a complex process, characterized by local leukocyte infiltration, expression and activation of matrix metalloproteinases, and apoptosis. Spontaneous decidualization (differentiation) of the stromal compartment precedes the cyclic shedding of the endometrium in various menstruating species but the mechanisms that link these processes are not understood. In this study, we identified FOXO1 as a key transcription factor responsible for mediating apoptosis of decidualized human endometrial stromal cells (HESCs) in response to progesterone withdrawal. We demonstrate that medroxyprogesterone acetate (MPA, a synthetic progestin) enhances the expression of FOXO1 in differentiating HESCs while simultaneously inducing cytoplasmic retention and inactivation of FOXO1. Withdrawal of MPA from decidualized HESCs results in rapid nuclear accumulation of FOXO1, increased BIM expression, a proapoptotic FOXO1 target gene, and cell death. Conversely, silencing of FOXO1 expression completely abolishes cell death induced by MPA withdrawal. In summary, the observation that differentiating HESCs become dependent on progesterone signaling for survival through induction and reversible inactivation of FOXO1 suggests a novel mechanism that links decidualization of the endometrium to menstruation.
Mol Endocrinol 2006 Jan
PMID:Progestins regulate the expression and activity of the forkhead transcription factor FOXO1 in differentiating human endometrium. 1612 51

Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by stereotypic host inflammatory and repair cellular responses; however, mechanisms regulating the resolution of ARDS are poorly understood. Here, we report the isolation and characterization of a novel population of mesenchymal cells from the alveolar space of ARDS patients via fiber-optic bronchoscopy with bronchoalveolar lavage (BAL). BAL was performed on 17 patients during the course of ARDS. Immunofluorescence staining and multiparameter flow cytometric analysis defined a population of alveolar mesenchymal cells (AMCs) that are CD45-/prolyl-4-hydroxylase+/alpha-smooth muscle actin+/-. AMCs proliferated in ex vivo cell culture for multiple passages; early passage (3-5) cells were subsequently analyzed in 13 patients. AMCs isolated from patients with persistent or nonresolving ARDS (ARDS-NR, n = 4) demonstrate enhanced constitutive activation of prosurvival signaling pathways involving PKB/Akt, FKHR, and BCL-2 family proteins compared with AMCs from patients with resolving ARDS (ARDS-R, n = 9). Exogenous transforming growth factor-beta1 markedly induces PKB/Akt activation in AMCs from ARDS-R. ARDS-NR cells are more resistant to serum deprivation-induced apoptosis compared with ARDS-R. This study identifies a novel population of mesenchymal cells that can be isolated from the alveolar spaces of ARDS patients. AMCs in patients with ARDS-NR acquire an activational profile characterized by enhanced prosurvival signaling and an antiapoptotic phenotype. These findings support the concept that apoptosis of mesenchymal cells may be an essential component of normal repair and resolution of ARDS and suggest that dysregulation of this process may contribute to persistent ARDS.
Am J Physiol Lung Cell Mol Physiol 2006 Mar
PMID:Constitutive activation of prosurvival signaling in alveolar mesenchymal cells isolated from patients with nonresolving acute respiratory distress syndrome. 1621 15

FGFRL1 is a novel member of the FGF receptor family. It is expressed at very low levels in a great variety of cell lines and at relatively high levels in SW1353 chondrosarcoma cells, MG63 osteosarcoma cells and A204 rhabdomyosarcoma cells. Screening of 241 different human tumors with the help of a cancer profiling array suggested major alterations in the relative expression of FGFRL1 in ovarian tumors. Five distinct ovary tumors were therefore analyzed by quantitative and competitive PCR. Several tumors were found to exhibit a significant decrease in the expression of FGFRL1 in the tumor tissue relative to the matched control tissue. One ovarian tumor showed a 25-fold increase in the relative expression. Since FGFRL1 appears to be involved in the control of cell proliferation and differentiation, its aberrant expression might contribute to the development and progression of ovarian tumors.
Int J Mol Med 2005 Dec
PMID:Aberrant expression of FGFRL1, a novel FGF receptor, in ovarian tumors. 1627 2

The genes of the piwi family are defined by conserved PAZ and Piwi domains and play important roles in stem-cell self-renewal, RNA silencing and translational regulation in various organisms. Both, mouse and human Piwil2 genes, members of the piwi gene family, are specifically expressed in testis. We report here enhanced expression of the human Piwil2 gene in testicular seminomas, but not in testicular non-seminomatous tumors. Expression of the Piwil2 gene was also found in different tumors examined, including prostate, breast, gastrointestinal, ovarian and endometrial cancer of human and in breast tumors, rhabdomyosarcoma and medulloblastoma of mouse. Therefore, Piwil2 can be categorized as a novel member of cancer/testis antigens. To identify genes activated by Piwil2, RNA isolated from NIH-3T3 cells expressing constitutively Piwil2 were compared with RNA samples from control NIH-3T3 cells using a cancer gene array. Induction of high-level expression of the antiapoptotic gene Bcl-X(L) was observed in cells expressing Piwil2. Furthermore, increased Bcl-X(L) expression correlated with increase of signal transducer and activator of transcription 3 (Stat3) expression. Gene silencing of Piwil2 with its small interference RNA suppressed Stat3 and Bcl-X(L) expression and induced apoptosis. A causal link between Piwil2 expression and inhibition of apoptosis and enhanced proliferation was demonstrated in cells expressing Piwil2. Furthermore, results of soft agar assay indicated that Piwil2 overexpression induced transformation of fibroblast cells. In summary, our results demonstrate that Piwil2 is widely expressed in tumors and acts as an oncogene by inhibition of apoptosis and promotion of proliferation via Stat3/Bcl-X(L) signaling pathway. Expression of Piwil2 in a wide variety of tumors could be a useful prognostic factor that could have also diagnostic and therapeutic implications.
Hum Mol Genet 2006 Jan 15
PMID:Stem-cell protein Piwil2 is widely expressed in tumors and inhibits apoptosis through activation of Stat3/Bcl-XL pathway. 1637 60


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