UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukocyte recruitment is a key step in the inflammatory reaction. Several changes in the cell morphology take place during lymphocyte activation and migration: spheric-shaped resting T cells become polarized during activation, developing a well defined cytoplasmic projection designated as cellular uropod. We found that the chemotactic and proinflammatory chemokines RANTES, MCP-1, and, to a lower extent, MIP-1 alpha, MIP-1 beta, and IL-8, were able to induce uropod formation and ICAM-3 redistribution in T lymphoblasts adhered to ICAM-1 or VCAM-1. A similar chemokine-mediated effect was observed during T cells binding to the fibronectin fragments of 38- and 80-kD, that contain the binding sites for the integrins VLA-4 and VLA-5, respectively. The uropod structure concentrated the ICAM-3 adhesion molecule (a ligand for LFA-1), and emerged to the outer milieu from the area of contact between lymphocyte and protein ligands. In addition, we found that other adhesion molecules such as ICAM-1, CD43, and CD44, also redistributed to the lymphocyte uropod upon RANTES stimulation, whereas a wide number of other cell surface receptors did not redistribute. Chemokines displayed a selective effect among different T cell subsets; MIP-1 beta had more potent action on CD8+ T cells and tumor infiltrating lymphocytes (TIL), whereas RANTES and MIP-1 alpha targeted selectively CD4+ T cells. We have also examined the involvement of cAMP signaling pathway in uropod formation. Interestingly, several cAMP agonists were able to induce uropod formation and ICAM-3 redistribution, whereas H-89, a specific inhibitor of the cAMP-dependent protein kinase, abrogated the chemokine-mediated uropod formation, thus pointing out a role for cAMP-dependent signaling in the development of this cytoplasmic projection. Since the lymphocyte uropod induced by chemokines was completely abrogated by Bordetella pertussis toxin, the formation of this membrane projection appears to be dependent on G proteins signaling pathways. In addition, the involvement of myosin-based cytoskeleton in uropod formation and ICAM-3 redistribution in response to chemokines was suggested by the prevention of this phenomenon with the myosin-disrupting agent butanedione monoxime. Interestingly, this agent also inhibited the ICAM-3-mediated cell aggregation, but not the cell adhesion to substrata. Altogether, these results demonstrate that uropod formation and adhesion receptor redistribution is a novel function mediated by chemokines; this phenomenon may represent a mechanism that significantly contributes to the recruitment of circulating leukocytes to inflammatory foci.
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PMID:Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix. Involvement of cAMP signaling pathway. 759 74

It has been shown that the intracellular cAMP levels were decreased in human malignant astrocytomas. On the other hand, various growth factors and their receptors were found to be overexpressed in these tumors. It is therefore intriguing as to whether there is interplay between the two phenomena in the modulation of the astrocytoma cell growth. In a basal medium consisting of 75% DMEM, 25% Ham's F-12 supplemented with 2% FBS, we show that the mitogenic effects of platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) on human astrocytoma cells were suppressed by dibutyryl-cAMP. Dibutyryl-cAMP alone neither potentiated nor inhibited the tumor cell growth. Further studies show that PDGF-induced receptor autophosphorylation in human astrocytoma cells is suppressed by increased intracellular cAMP levels as measured by immunoprecipitation with anti-PDGF receptor and antiphosphotyrosine antibodies. Our results indicate that there is antagonistic interplay between the receptor tyrosine kinase pathway and cAMP-dependent protein kinase pathway in the control of the malignantly transformed glial cells. A reduced cAMP level seen in many human astrocytoma cells may favor their response to growth factor mitogenesis.
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PMID:Increased intracellular cyclic AMP levels suppress the mitogenic responses of human astrocytoma cells to growth factors. 762 68

Metastatic Lewis lung carcinoma (LLC-LN7) cells have increased protein kinase A (PKA) activity and are more invasive in vitro than are non-metastatic (LLC-C8) cells. To determine whether PKA mediates the in vitro invasiveness and in vivo metastatic capabilities of these tumor cells, the LLC variants were stably transfected to over-express the C alpha subunit of PKA, and thus to have increased PKA activity, or to express a mutant cAMP-resistant PKA R1 alpha subunit which blocks PKA activation. Wild-type LLC-LN7 tumor cells were invasive in vitro and in vivo, recurred after tumor excision and metastasized to the lungs. However, they lost these properties after transfection to express the mutant R1 alpha that blocks PKA activation. The non-invasive, non-recurring and non-metastatic LLC-C8 cells gained the capacity to invade, to recur following tumor excision and to metastasize when transfected to express the PKA C alpha subunit.
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PMID:Regulation of Lewis lung carcinoma invasion and metastasis by protein kinase A. 770 21

Endogenously generated or exogenously applied nitric oxide (NO) redox species induce apoptotic cell death in murine RAW 264.7 macrophages. Activation of the inducible NO synthase by incubation of cells with a combination of lipopolysaccharide and interferon-gamma produced internucleosomal DNA fragmentation and morphological alterations, i.e., chromatin condensation, indicative of apoptotic cell death. These alterations, reflecting the production of NO, were prevented by an inhibitor of NO synthase, NG-monomethyl-L-arginine. Moreover, NO derived from endogenous or exogenous sources caused accumulation of the tumor suppressor gene p53. Proposing a link between NO generation and DNA fragmentation, we investigated interfering biochemical signaling pathways. Therefore, we tested the ability of four NO-releasing compounds [sodium nitroprusside (SNP), 3-morpholinosydnonimine (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP), and S-nitrosoglutathione (GSNO)] to cause specific DNA fragmentation. All NO donors induced DNA fragmentation in a time- and concentration-dependent manner. However, substance-specific differences became obvious. After an 8-hr incubation period, GSNO proved to be the strongest apoptotic inducer, whereas SIN-1 was much less active. Apoptosis was rapid with GSNO and SNP, yielding specific DNA fragments after 4 hr and 5 hr, respectively. In contrast, SNAP and SIN-1 produced DNA fragmentation after considerable lag times of 9 hr and 14 hr, respectively. Furthermore, an inhibitory effect of protein kinase C (PKC) and cAMP-dependent protein kinase became apparent. 12-O-Tetradecanoylphorbol-13-acetate, an activator of PKC, inhibited DNA fragmentation by all four NO donors, whereas PKC inhibitors such as staurosporine and calphostin C sensitized macrophages to apoptosis induced by SNP and GSNO. Lipophilic cAMP analogues suppressed SNP-, SIN-1, and SNAP-induced DNA fragmentation. Thus, our study suggests the existence of specific down-modulatory mechanisms related to NO-induced apoptotic DNA fragmentation.
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PMID:Nitric oxide-induced apoptosis in RAW 264.7 macrophages is antagonized by protein kinase C- and protein kinase A-activating compounds. 772 36

We recently identified a novel 8-kDa transmembrane protein, Mat-8, that is expressed in a subset of murine breast tumors. We have now cloned a cDNA encoding the human version of Mat-8 and show that it is expressed both in primary human breast tumors and in human breast tumor cell lines. The extracellular and transmembrane domains of Mat-8 are homologous to those of phospholemman (PLM), the major plasmalemmal substrate for cAMP-dependent protein kinase and protein kinase C in several different tissues. PLM, which induces chloride currents when expressed in Xenopus oocytes, contains consensus phosphorylation sites for both cAMP-dependent protein kinase A and protein kinase C in its cytoplasmic domain. In contrast, the cytoplasmic domain of Mat-8 contains no such consensus phosphorylation sites and is, in fact, unrelated to the cytoplasmic domain of PLM. RNA blot analysis reveals that Mat-8 and PLM exhibit distinct tissue-specific patterns of expression. We show that expression of Mat-8 in Xenopus oocytes induces hyperpolarization-activated chloride currents similar to those induced by PLM expression. These findings suggest that Mat-8 and PLM, the products of distinct genes, are related proteins that serve as Cl- channels or Cl- channel regulators but have different roles in cell and organ physiology.
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PMID:Mat-8, a novel phospholemman-like protein expressed in human breast tumors, induces a chloride conductance in Xenopus oocytes. 783 47

We previously demonstrated that the mitochondrial peripheral-type benzodiazepine receptor (PBR) is coupled to hormone-activated steroidogenesis by regulating the intramitochondrial cholesterol transport, the rate-determining step of steroid biosynthesis. In the present study we examined whether PBR is the site of hormone action using the hCG-responsive MA-10 mouse Leydig tumor cell line as a model system. Within 15 sec of the addition of hCG to Leydig cells a 3-fold cAMP-dependent increase in PBR binding was observed. This rapid increase returned to basal levels within 60 sec. No effect was observed after 1 min in the continued presence of hCG. Scatchard analysis revealed that in addition to the known high affinity (5.0 nM) benzodiazepine-binding site, a second, hormone-induced, higher affinity (0.2 nM) benzodiazepine-binding site appeared. We then examined whether in such a short time frame steroid synthesis occurs. Fifteen-second incubation of MA-10 cells with the inhibitor of cholesterol metabolism aminoglutethimide together with hCG also resulted in an increased rate of pregnenolone formation by their isolated mitochondria that were washed and incubated in aminoglutethimide-free buffer. The dose response of benzodiazepine binding to hCG closely parallels the increase in steroid formation by the mitochondria of stimulated cells. Addition of the selective inhibitor of cAMP-dependent protein kinase, H-89, completely blocked hormone-induced PBR binding and steroid formation, whereas addition of the inactive analog H-85 was without any effect. The addition of flunitrazepam, a benzodiazepine previously shown to inhibit the trophic hormone action on steroidogenesis, completely abolished the hCG-induced rapid stimulation of steroid synthesis. These results demonstrate that in MA-10 cells, the most rapid effect described thus far of hCG and cAMP, is the transient induction of a higher affinity benzodiazepine-binding site, which occurs concomitantly with an increase in the rate of steroid formation. This, in turn, suggests that these hormones alter PBR to activate cholesterol delivery to the inner mitochondrial membrane and subsequent steroid formation.
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PMID:Acute action of choriogonadotropin on Leydig tumor cells: induction of a higher affinity benzodiazepine-binding site related to steroid biosynthesis. 792 20

Treatment of F344 rats with diethylstilbestrol (DES) for 1-2 months induces a prolactin (PRL)-secreting pituitary adenoma. After 8 weeks of DES treatment, we have shown that the ratio of regulatory subunits of the cAMP-dependent protein kinase (RI/RII) increased in the tumors. Presently we report the variations in RI/RII ratio, pituitary weight, DNA content, serum PRL, nuclear estrogen receptor (E2R) and of ornithine decarboxylase (ODC) activity from the time of DES pellet implantation until 8 weeks. Pituitary weight, DNA content and serum PRL rose significantly at 4 weeks with a maximum at 6-8 weeks, and significantly correlated with each other. E2R and ODC activity increased from week 1 onwards, with a maximum at 2 weeks and decreased at 8 weeks. Both variables showed a positive correlation but neither E2R nor ODC activity correlated with pituitary weight, DNA or serum PRL. Values for RI remained stable with time, but RII decreased progressively. The RI/RII ratio was maintained around unity between 1-4 weeks, increasing to 1.6-2 thereafter. This ratio positively correlated with pituitary weight and DNA. It is suggested that during tumor induction by estrogen in a sensitive strain of rats, growth signals with different time-courses become activated. Increases in pituitary weight and DNA content, indicators of mammotroph hypertrophy and hyperplasia, were preceded by early rises in E2R and ODC activity. Increases in the RI/RII ratio accompanied the adenomatous change, suggesting their role in cell transformation after 6 weeks of estrogen exposure.
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PMID:Biochemical parameters in the anterior pituitary during the course of tumorigenesis induced by diethylstilbestrol treatment. 798 Nov 27

We report that the small tumor (small-t) antigen of simian virus 40 (SV40) forms complexes with nuclear protein phosphatase 2A (PP2A) and regulates the phosphorylation and transcriptional transactivation function of the cyclic AMP (cAMP)-regulatory element binding protein (CREB). PP2A coimmunoprecipitated with small t from nuclear extracts from HepG2 cells expressing small t or from rat liver nuclear extracts to which recombinant small t was added. Protein phosphatase 1 was not detected in small-t immunoprecipitates. In HepG2 cells expressing small t, dibutyryl-cAMP (Bt2cAMP) stimulated the phosphorylation of CREB 65-fold, whereas CREB phosphorylation was stimulated only 5- to 8-fold by Bt2cAMP in cells not expressing small t. Small t also inhibited the dephosphorylation of cAMP-dependent protein kinase (PKA)-phosphorylated CREB in rat liver nuclear extracts. In cells expressing small t, Bt2cAMP-stimulated transcription from the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter was enhanced over the level of transcription from the PEPCK promoter in cells not expressing small t. Small t also enhanced Bt2cAMP-stimulated transcription from a Gal4-responsive promoter in cells expressing a chimeric protein containing the Gal4 DNA-binding domain linked to the CREB transactivation domain. However, small t did not stimulate transcription either from a 5' deletion mutant of the PEPCK promoter that is not able to bind CREB or from the Gal4-responsive promoter in the absence of the Gal4-CREB protein. These data suggest that small t enhances Bt2cAMP-stimulated gene transcription by inhibiting the dephosphorylation of PKA-phosphorylated CREB by nuclear PP2A. These findings support previous observations that nuclear PP2A is the primary phosphatase that dephosphorylates PKA-phosphorylated CREB.
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PMID:Simian virus 40 small tumor antigen inhibits dephosphorylation of protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation. 806 21

MCF-10A is a spontaneously immortalized, non-transformed human mammary epithelial cell line. We have recently obtained MCF-10A clones (MCF-10A HE cells) that are transformed following over-expression of both a human point-mutated c-Ha-ras and the c-erbB-2 proto-oncogenes. Two isoforms of the cAMP-dependent protein kinase (cAK) have been described in mammalian cells. Enhanced levels of type-I cAK (cAKI) are generally found in tumor cells. To determine whether inhibition of cAKI expression may interfere with ras and erbB-2 oncogene-induced transformation of human mammary epithelial cells, we have tested the effects of 2 agents that specifically down-regulate cAKI, such as 8-chloro-cAMP and an anti-sense oligodeoxynucleotide targeted against the RI alpha regulatory subunit of cAKI on MCF-10A HE cells. Treatment of MCF-10A HE cells with 8-chloro-cAMP induces a dose-dependent growth inhibition under both monolayer and soft-agar growth conditions, that is correlated with an accumulation of MCF-10A HE cells in G0/G1 phases of the cell cycle and a reduction of the number of cells in S phase. In contrast, 8-chloro-cAMP has no effect on MCF-10A cell growth. Furthermore, 8-chloro-cAMP treatment of MCF-10A HE cells induces a 4- to 6-fold reduction in p185erbB-2 expression and brings p21ras expression to levels comparable to those found in MCF-10A cells. Treatment of MCF-10A HE cells with an RI alpha anti-sense oligodeoxynucleotide determines a comparable inhibition of both anchorage-dependent and anchorage-independent cell growth. Our results suggest that cAKI may act as a mediator of ras and erbB-2 oncogene action in human breast cells and that interference with cAKI action provides a potential tool for inhibiting the growth-promoting effects of these oncogenes.
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PMID:Down-regulation of RI alpha subunit of cAMP-dependent protein kinase induces growth inhibition of human mammary epithelial cells transformed by c-Ha-ras and c-erbB-2 proto-oncogenes. 809 73

The true rate-limiting step in steroidogenesis is the delivery of cholesterol to the inner mitochondrial membrane where it is converted to pregnenolone by the cholesterol side-chain cleavage complex. This process is known to require de novo protein synthesis. We have previously described the synthesis of a family of 37, 32, and 30 kilodalton mitochondrial proteins in response to hormone stimulation in MA-10 mouse Leydig tumor cells and have proposed that these proteins are involved in the acute regulation of steroidogenesis. In this study we have used two subclones of MA-10 cells to further demonstrate the correlation between the quantity of these proteins and the production of steroids in response to hormone treatment. One of these, designated MA-10(K3), has been transfected with a mutant gene of the type 1 regulatory subunit of the cAMP-dependent protein kinase under the control of a metallothionein promoter, whereas the other, designated MA-10(P+29), is a constitutive overproducer of a cAMP-phosphodiesterase (PDE). MA-10 parent cells designated (P), produce large amounts of progesterone in response to LH, human CG, and (Bu)2cAMP. The MA-10(K3) cells, on the other hand, whereas significantly higher than controls, produce much less steroid than the parent cells in response to hormone stimulation. Activation of the mutant gene with Zn+2 results in yet a further decrease in the amount of steroid produced. The MA-10(P+29) cells display greatly reduced progesterone production when stimulated with LH, because of the presence of high amounts of PDE, but return to maximally stimulated levels when a PDE inhibitor is present. Quantitation of the synthesis of the mitochondrial proteins described above in MA-10(K3) cells in the presence and absence of Zn+2 and in MA-10(P+29) cells in the presence and absence of PDE inhibitor clearly demonstrate that the amount of the 30 kilodalton mitochondrial proteins present in these cells closely parallels that of progesterone production. The high degree of correlation between the appearance and quantity of these mitochondrial proteins and the production of steroids make them strong candidates for the putative proteins involved in acute regulation of steroidogenesis.
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PMID:The use of genetic manipulation of MA-10 Leydig tumor cells to demonstrate the role of mitochondrial proteins in the acute regulation of steroidogenesis. 838 3

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