Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The non-12-O-tetadecanoylphorbol-13-acetate (TPA)-type tumor promoters, okadaic acid (OA) and calyculin-A (CAL-A), which neither interact with the phorbol ester receptor nor directly activate protein kinase C, mimic the stimulatory effects of and thapsigargin on hydroperoxide (HPx) production in mouse epidermis in vivo. The time course and dose dependency for the stimulation of HPx production by O and TPA are similar. HPx production is maximally stimulated 16 h after two applications of 2 nmol of OA at a 48-h interval. However CAL-A is a stimulator of HPx production about 4 times more potent than OA or TPA. Combinations of TPA and OA or CAL-A have subadditive effects on HPx production. The discrepancies between the abilities of various serine/threonine protein phosphatase (PP) inhibitors to stimulate HPx production suggest that PP inhibition alone is not sufficient for this response. Cycloheximide, Ca2+ antagonists, oxypurinol, diphenyliodonium, nordihydroguaiaretic acid, bromophenacyl bromide, antiinflammatory agents, and antihistamines block or decrease OA-stimulated HPx production. Although most of these inhibitors may have more than one action, their effects suggest that protein synthesis, Ca2+, xanthine oxidase and NADPH oxidase activities, the lipoxygenase pathway of arachidonic acid metabolism, and vascular permeability may be involved in the inflammatory and HPx responses that occur after tumor promoter treatment. The increased HPx-producing activity of the epidermis, therefore, may be a common event resulting from the inflammatory and tumor-promoting actions of diverse TPA- and non-TPA-type agents.
Cancer Lett 1996 Jan 02
PMID:Ability of okadaic acid and other protein phosphatase inhibitors to mimic the stimulatory effects of 12-O-tetradecanoylphorbol-13-acetate on hydroperoxide production in mouse epidermis in vivo. 855 15

A radiation-inducible immediate-early gene, IEX-1, was identified and characterized in human squamous carcinoma cells. Sequence analysis revealed 156-amino acid nucleotides, encoding a protein of Mr 20,000. The protein is glycosylated (Mr approximately 27,000) in the presence of microsomal membranes. Northern analysis reveals a 1.2-kb transcript. Treatment with cycloheximide was associated with superinduction of this transcript suggesting that it is an immediate-early gene. The abundance of IEX-1 mRNA increased rapidly after exposure of the cells to ionizing radiation (2-10 Gy), reaching a maximum by 15 min and returning subsequently to basal levels by 4 h. Expression of IEX-1 was also induced significantly by the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol-13-acetate (TPA), the protein phosphatase inhibitor okadaic acid, and tumor necrosis factor-alpha, whereas treatment of cells with UV light and H2O2 had little effect on IEX-1 expression. Cells depleted of PKC by prolonged incubation with TPA showed no attenuated IEX-1 response to tumor necrosis factor-alpha. This is the first report of IEX-1, a radiation-inducible glycosylated human protein, whose expression can be mediated through multisignal transduction pathways.
Cancer Res 1996 Apr 01
PMID:Identification and characterization of a radiation-inducible glycosylated human early-response gene. 860 92

To investigate early signaling events responsible for regulation of programmed cell death or apoptosis, we studied campothecin (a topoisomerase I inhibitor)-mediated apoptosis in the human promyelocytic leukemia cell line HL60. We demonstrate a tight correlation between protection of HL60 cells from apoptosis-associated internucleosomal DNA fragmentation by specific protease inhibitors or protein phosphatase inhibitors, with early tyrosine phosphorylation of a single protein substrate with a molecular weight of approximately 42,000. Exposure to protease inhibitors that did not protect HL60 cells from DNA fragmentation did not result in phosphorylation of this substrate. Likewise, a protein tyrosine kinase inhibitor that did not interfere with specific phosphorylation did not prevent DNA fragmentation. Taken together, these results suggest that phosphorylation of a Mr 42,000 substrate constitutes an important signaling event that may participate in regulation of the apoptotic response.
Cancer Res 1996 Sep 01
PMID:Protease inhibitors induce specific changes in protein tyrosine phosphorylation that correlate with inhibition of apoptosis in myeloid cells. 875 57

The expression of the three catalytic subunits of protein phosphatase (PP) type 1 and 2A, PP1 alpha, PP1 gamma 1, and PP2AC, was examined in osteogenic tumors and soft tissue tumors by immunohistochemical analysis. The percentage of cells stained positively with antiserum against PP1 catalytic subunit isoform PP1 gamma 1, was significantly higher in malignant osteogenic tumors (chondrosarcoma, osteosarcoma, and Ewing's sarcoma) and in malignant soft tissue tumors (liposarcoma and malignant fibrous histiocytoma [M.F.H.]) than in benign tumors (osteochondroma, osteoblastoma, ossifying fibroma, enchondroma and lipoma). Furthermore, the malignant tumor lesions showed a markedly high number of cells in the S-phase fraction of the cell cycle, as compared to benign tumors. These results suggest that PP1 gamma 1 is involved in the accelerated growth of malignant tumor cells.
 ...
PMID:Role of protein phosphatase in malignant osteogenic and soft tissue tumors. 886 68

Hox11 is an orphan homeobox gene that controls the genesis of the spleen. HOX11 is also oncogenic, having been isolated from a chromosomal breakpoint in human T-cell leukaemia. Transgenic mice that redirected HOX11 to the thymus demonstrated cell-cycle aberration and progression to malignancy. We observed that the protein HOX11 interacted with protein serine-threonine phosphatase 2A catalytic subunit (PP2AC), as well as protein phosphatase 1 (PP1C) in mammalian cells. Inhibition of PP2A can regulate the cell cycle and control the activation of maturation-promoting factor in Xenopus oocytes. Microinjection of HOX11 into Xenopus oocytes arrested at the G2 phase of the cell cycle promoted progression to the M phase. G2 arrest can be induced by gamma-irradiation, but is eliminated by expression of HOX11 within a T-cell line. Thus HOX11 is a cellular oncogene that targets PP2A and PP1, both of which are targets for oncogenic viruses and chemical tumour promoters. This interaction suggests a mechanism by which a homeobox can alter the cell cycle.
 ...
PMID:HOX11 interacts with protein phosphatases PP2A and PP1 and disrupts a G2/M cell-cycle checkpoint. 900 95

The role of protein phosphatase-2A (PP-2A) in regulating the motility and adhesion of human head and neck squamous cell carcinomas (HNSCC) was investigated. Immunofluorescent staining of these HNSCC cells showed PP-2A can co-localize with microtubules. That the PP-2A influences motility was shown by the increase in HNSCC cell migration through laminin and vitronectin when PP-2A was selectively inhibited with low dose okadaic acid, and by the reduction in invasion through these same matrix components by elevators of PP-2A activity. Motility of HNSCC cells through collagen I or fibronectin was not modulated by PP-2A. The reduction in HNSCC migration through vitronectin or laminin that resulted from treatment with PP-2A elevators was associated with an increase in cellular adhesiveness to these same ECM components. These studies show the association of PP-2A with the cellular cytoskeleton and its role in restricting the invasiveness of tumor cells through select extracellular matrix components.
Cancer Lett 1997 Jan 01
PMID:Protein phosphatase-2A association with microtubules and its role in restricting the invasiveness of human head and neck squamous cell carcinoma cells. 902 32

Breast cancer is one of the most common malignancies of women. Assessing the biological parameters of malignant tumors may facilitate predictions of clinical outcome. The expression of the three catalytic subunits of protein phosphatase (PP) type 1, PP1 alpha, PP1 gamma 1 and PP1 delta, as well as the one catalytic subunit of PP type 2, PP2AC, were examined in ten cases of mammary dysplasia, ten cases of fibroadenoma and 12 cases of invasive ductal carcinoma, using immunohistochemical analysis. Moreover, we measured the S-phase fraction of the cell cycle for use as a marker value of cell growth, using flow cytometric analysis. The percentage of proliferating cells that stained positive with antisera against PP1 gamma 1 was significantly higher in invasive ductal carcinoma than in mammary dysplasia and fibroadenoma. Furthermore, invasive ductal carcinoma showed a markedly high number of tumor cells in the S-phase of the cell cycle, as compared to mammary dysplasia and fibroadenoma. Our results indicate that PP1 gamma 1 may be involved in the accelerated growth of malignant cells in breast tumors.
Cancer Lett 1997 Jan 30
PMID:Enhanced expression of PP1 gamma 1, a catalytic subunit isoform of protein phosphatase type 1, in invasive ductal carcinoma of the breast. 906 38

Okadaic acid (OA) is an inhibitor of serine/threonine protein phosphatase (PP) and a tumor promoter in mouse skin carcinogenesis. According to Carcinogenesis Division, National Cancer Center Research Institute, OA induces various genetic alterations, such as loss of exogenous genes, sister chromatid exchanges and diphtheria toxin resistant mutants, although there is no evidence showing that it interacts with DNA directly or produces active oxygen under the conditions used. In this study, minisatellite, which is a hotspot of recombination, was investigated regarding the induction of alteration and instability by OA. It was also attempted to elucidate the roles of minisatellite instability in carcinogenesis. NIH3T3 cells were cultured either with or without OA, subcloned and DNA from each clone was subjected to fingerprint analysis using the Pc-1 minisatellite probe. The frequency of minisatellite recombination was 29% in OA-treated cells, as opposed to 3% in nontreated cells. Furthermore, OA-treated cells exhibited tumorigenicity in nude mice. Minisatellite fingerprint analysis of clones obtained from the tumors revealed that those tumors had acquired minisatellite instability. These mechanisms may be involved in tumor promotion by OA.
 ...
PMID:[Minisatellite instability induced by okadaic acid]. 912 47

Most cancer cells have increased levels of telomerase activity implicated in cell immortalization. Activation of telomerase, a ribonucleoprotein complex, catalyzes the elongation of the ends of mammalian chromosomal DNA (telomeres), the length of which regulates cell proliferation. Currently, how telomerase is regulated in cancer is not yet established. The present study shows that telomerase activity is regulated by protein phosphorylation in human breast cancer cells. Incubation of cell nuclear telomerase extracts with protein phosphatase 2A (PP2A) abolished the telomerase activity; in contrast cytoplasmic telomerase activity was unaffected, and protein phosphatases 1 and 2B were ineffective. Inhibition of telomerase activity by PP2A was both concentration- and time-dependent and was prevented by the protein phosphatase inhibitor okadaic acid. In addition, nuclear telomerase inhibited by PP2A was reactivated by endogenous protein kinase(s) in the presence of ATP, but not in the presence of ATPgammaS. Furthermore, telomerase activity in cultured human breast cancer PMC42 cells was stimulated by okadaic acid, consistent with a role for PP2A in the regulation of telomerase activity in intact cells. These findings suggest that protein phosphorylation reversibly regulates the function of telomerase and that PP2A is a telomerase inhibitory factor in the nucleus of human breast cancer cells.
 ...
PMID:Protein phosphatase 2A inhibits nuclear telomerase activity in human breast cancer cells. 920 74

Certain oligodeoxynucleotides (ODN) containing cytosine followed by guanosine (CpG) protect B cells from apoptosis, and induce B-cell proliferation and cytokine production. We investigated the effect of phosphorothioate CpG-containing ODNs (5'-ATAATCGACGTTCAAGCAAG-3' or 5'-TCCATGACGTTCCTGACGTT-3') and control ODNs (which did not contain CpG) on apoptosis and cell growth in WEHI 231 murine B lymphoma cells. Anti-surface (alpha-s)IgM antibody induces 40-60% DNA degradation and growth arrest of WEHI 231 cells in 24 h. Both of these effects were substantially reversed by 30 ng/ml CpG-ODN added up to 8 hr after alpha-sIgM. Control ODNs not containing the CpG motif were without effect. We explored various hypotheses to account for these effects. The phorbol ester, 12-O-tetradecanoyl phorbol-13-acetate, inhibits apoptosis induced by alpha-sIgM, but the anti-apoptotic effect of CpG-ODN was not affected by inhibitors of protein kinase C, indicating that CpG-ODN does not act via protein kinase C. CpG-ODN inhibited apoptosis and growth arrest induced by C2- and C8-ceramide, sphingomyelinase and an intracellular Ca2+ pump inhibitor thapsigargin, indicating that inhibition is not mediated via suppression of the ceramide cycle or suppression of Ca2+ mobilization. CpG-ODN partially inhibited apoptosis induced by okadaic acid, a protein phosphatase inhibitor, and by menadione, a free radical generator. CpG-ODN also inhibited apoptosis and growth arrest induced by ultraviolet-irradiation, glucocorticoid, vinca alkaloids, and doxorubicin. CpG-ODN significantly protected cells from DNA fragmentation induced by alpha-sIgM in the presence of cycloheximide, but cycloheximide itself induces apoptosis which was unaffected by CpG-ODN. These results suggest that CpG-ODNs powerfully modulate the process by which immune cells are committed to death or proliferation by a mechanism acting on distal cell signalling events. CpG-ODNs may be able to decrease immunosuppression in patients undergoing cancer chemotherapy.
 ...
PMID:Unmethylated CpG-containing oligodeoxynucleotides inhibit apoptosis in WEHI 231 B lymphocytes induced by several agents: evidence for blockade of apoptosis at a distal signalling step. 937 99


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>