Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twelve x-ray-induced transcripts (xips), differentially expressed 8- to 230-fold in x-irradiated versus unirradiated radioresistant human melanoma (U1-Mel) cells, were isolated as cDNA clones (xip1 through xip12) after four rounds of differential hybridization. Northern analyses revealed rare, medium, and abundant xips, ranging in size from 1.2 to 10 kb. All transcripts were transiently expressed and induced by low, but not by high (> 600 cGy), doses of radiation. Three transcripts (xip4, -7, and -12) were induced only by ionizing radiation, and many (i.e., xip1, -2, -3, -5, -6, -8, -9, -10, and -11) were also induced by UV irradiation or phorbol 12-myristate 13-acetate. Heat shock did not induce any of the xips, but it decreased basal levels of xip4, -7, -11, and -12. Three xip cDNA clones were identified as encoding thymidine kinase, DT diaphorase, and tissue-type plasminogen activator. The remaining nine cDNA clones showed little homology to known genes. Three clones contained regions homologous to c-fes/fps protooncogene, recombination activating gene 1, or the human angiogenesis factor gene. X-ray-inducible genes may function in damaged cells to regulate DNA repair, apoptosis, mutagenesis, and carcinogenesis.
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PMID:Isolation of x-ray-inducible transcripts from radioresistant human melanoma cells. 834 36

In contrast to the central nervous system (CNS), the peripheral nervous system (PNS) displays an important regenerative ability which is dependent, at least in part, on Schwann cell properties. The mechanisms which stimulate Schwann cells to adapt their behavior after a lesion to generate adequate conditions for PNS regeneration remain unknown. In this work, we report that adult rat dorsal root ganglion (DRG) neurons are able, after a lesion performed in vivo or when they are dissociated and cultured in vitro, to synthesize transforming growth factor beta (TGF beta), a pleiotropic growth factor implicated in wound healing processes and in carcinogenesis. This TGF beta is tentatively identified as the beta-1 isoform. Adult rat DRG neurons release a biologically active form of TGF beta which is able to elicit multiple Schwann cell responses including a stimulation to proliferate. Moreover, purified TGF beta-1 produces a Schwann cell morphology alteration and decreases the secretion of tissue-type plasminogen activator (tPA) and enhances the secretion of plasminogen activator inhibitor (PAI) by Schwann cells. This generates conditions which are thought to favor a successful neuritic regrowth. Furthermore, purified TGF beta-1 stimulates type IV collagen mRNA expression in Schwann cells. This subtype of collagen is associated with the process of myelinization. Finally, TGF beta-1 decreases nerve growth factor (NGF) mRNA expression by Schwann cells, an effect which could participate in the maintenance of a distoproximal NGF gradient during nerve regeneration. We propose that neuronal TGF beta plays an essential role as a neuronoglial signal that modulates the response of Schwann cells to injury and participates in the successful regeneration processes observed in the PNS.
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PMID:Transforming growth factor beta as a neuronoglial signal during peripheral nervous system response to injury. 842 35

Carcinogenesis in the human colon is associated with a marked increase of urokinase type plasminogen activator and a decrease of tissue type plasminogen activator. This study was performed to determine the concentrations of urokinase type plasminogen activator and tissue type plasminogen activator in normal tissue and carcinomas along the upper part of the gastrointestinal tract. Activity and antigen levels of both activators were determined in homogenates of endoscopically obtained biopsies from normal and carcinomatous tissues. Although the concentrations of tissue type plasminogen activator and urokinase type plasminogen activator in normal squamous epithelium of the oesophagus were low compared with those in columnar epithelium from the stomach, the urokinase type plasminogen activator/tissue type plasminogen activator antigen ratio of the different locations showed hardly any difference. Significant but heterogeneous increases were found in urokinase type plasminogen activator concentrations of biopsy specimens originating from carcinomas of both epithelial cell types. A decrease in tissue type plasminogen activator concentrations, as found in human colon carcinomas, could only be shown in carcinomas of columnar epithelium origin but not in squamous cell carcinomas of the oesophagus. The increase of urokinase type plasminogen activator and urokinase type plasminogen activator/tissue type plasminogen activator antigen ratio and the decrease of tissue type plasminogen activator in the carcinomas did not show a significant correlation with known prognostic determinants as differentiation grade, TNM classification, intestinal metaplasia, inflammation, and ulceration. The heterogeneous increase of urokinase type plasminogen activator in oesophageal and stomach carcinomas, together with the recently described association of urokinase type plasminogen activator in tissue extracts of breast carcinomas with aggressiveness and prognosis, may be relevance to prognostic studies, may be of relevance to prognostic studies in oesophageal and gastric cancer.
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PMID:Plasminogen activators in normal tissue and carcinomas of the human oesophagus and stomach. 843 57

Long-term H. pylori associated gastritis is recognized as a pathogenic factor in gastric carcinogenesis. In gastric carcinomas the amount and activity of the tissue-type plasminogen activator (t-PA) have been reported to be decreased, whereas those of the urokinase-type plasminogen activator (u-PA) were increased, contributing to the neoplastic and invasive process. The present study was performed to determine t-PA and u-PA levels and activity in gastric mucosa from 102 patients and to investigate whether these levels are influenced by H. pylori infection. The antigen concentration and activity of t-PA and u-PA in corpus mucosa were low (P < 0.001) compared with those in antral mucosa, although for the u-PA activity this did not reach statistical significance. In H. pylori-associated antral gastritis the mucosal t-PA antigen concentration and activity were found to be decreased (P < 0.001) compared with normal mucosa, whereas in H. pylori-associated pangastritis the corpus t-PA levels were not affected. The antigen concentration and activity of u-PA were found to be significantly (P < 0.005) increased, both in H. pylori-associated gastritis of antrum and corpus mucosa. Levels of u-PA in histologically normal corpus mucosa of patients with an H. pylori-associated antral gastritis were also found to be increased (P < 0.05). In conclusion, the alterations in the plasminogen activator profile found in H. pylori-associated gastritis, ie, a decrease in t-PA and an increase in u-PA, show a similar tendency as the previously found alterations in gastric carcinomas, which provides additional support for the possible involvement of H. pylori-associated gastritis in the pathogenesis of gastric carcinoma.
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PMID:Gastric mucosal plasminogen activators in Helicobacter pylori infection. 876 82

Activation of mitogen-activated protein kinase (MAPK) results in pleiotropic effects such as modulation of the transcription and activation of enzymes involved in signal transduction. One such enzyme is the cytoplasmic phospholipase A(2) (cPLA(2)), which releases arachidonic acid (AA). AA is the precursor of prostaglandins and leukotrienes, two inflammatory mediators, which regulate gene expression and protein kinase (PK) activity. Fumonisin B(1) (FB(1)) was shown to increase PKC translocation and stimulate MAPK. We have investigated the effect of FB(1) on the AA cascade in a human epithelial cell line and the signal transduction pathway regulating PLA(2) activation. We observed that FB(1) stimulated cPLA(2) activity and increased AA release by a mechanism independent of PKC activation and that the activation of cPLA(2) is a two-step process: the first is phosphorylation of cPLA(2) by MAPK; the second is a consequence of the increase in sphingosine inside and outside the cells after 2 h, which is known to induce a rise in intracellular free calcium. Overall, this suggests that the effect of FB(1) on cells is partially dependent on the action of FB(1) on the enzymes involved in the cell cycle, such as MAPK and PKA, and on bioactive fatty acids, such as the prostaglandins and leukotrienes, and also on disruption of sphingolipid metabolism. In addition, we have observed down-regulation of cPLA(2) activity and AA metabolism by a mechanism involving prostaglandin production, cAMP synthesis and PKA activation.
Carcinogenesis 1999 Sep
PMID:Activation of mitogen-activated protein kinase by fumonisin B(1) stimulates cPLA(2) phosphorylation, the arachidonic acid cascade and cAMP production. 1046 11

To elucidate the possible inhibitory effect of a novel carboxamide derivative (IS-741) on biliary carcinogenesis, Syrian hamsters were subjected to cholecystoduodenostomy and ligation of the distal end of the common duct, and then given a regular diet (group I) or a diet containing 200 p.p.m. of IS-741 (group II). All hamsters were subcutaneously injected with N-nitrosobis(2-oxopropyl)amine until 10 weeks after surgery, and continued to feed on their respective dietary regimen until termination of the experiment at 16 weeks after surgery. Biliary adenocarcinomas were evaluated histologically. Non-cancerous and cancerous hepatobiliary tract tissues were analyzed for phospholipase A(2) (PLA(2)) activity, myeloperoxidase (MPO) activity, and the concentrations of prostaglandin (PG), i.e., prostaglandin E(2), 6-ketoprostaglandin F(1)alpha and thromboxane B(2). IS-741 significantly inhibited the development and multiplicity of hepatobiliary adenocarcinomas and reduced the proliferating cell nuclear antigen labeling indices in non-cancerous hepatobiliary tissues, compared with group I. The anti-cancerous effect of IS-741 was associated with a significant inhibition of PLA(2) and MPO levels in non-cancerous tissues of the extrahepatic biliary tract and the liver, and in cancerous tissue of the liver. Furthermore, IS-741 reduced the production of PGs in non-cancerous hepatobiliary tissues, compared with group I. Although the precise mechanism of action of IS-741 in preventing biliary tumorigenesis remains to be elucidated, it is likely to be related to modulation of arachidonic acid metabolism and/or suppression of neutrophil accumulation.
Carcinogenesis 2000 Aug
PMID:Chemoprevention of biliary carcinogenesis in syrian hamsters by the novel carboxamide derivative IS-741 after initiation with N-nitrosobis(2-oxopropyl)amine (BOP). 1091 Sep 46

The growth factor receptor-dependent protein kinase Raf-1 is activated by GTP-bound Ras, thereby activating the mitogen-activated protein kinase pathway. To study the role of Raf in transformation we transduced Rat-1 cells with a tetracycline-regulatable retroviral vector encoding the constitutively active oncogenic C-terminal fragment of the human Raf-1 protein. Using subtractive hybridization of mRNAs from induced and noninduced cells and robot-assisted screening by complex hybridization, Raf-induced genes with various different characteristics of induction were investigated. Among the strongly induced genes were those involved in carcinogenesis such as metalloproteinases 3, 10 and 13, cathepsin L, ornithine decarboxylase, and putative tumor-suppressing genes such as monocyte chemoattracting protein 1, interferon-induced protein 10, a recently identified 2'-5' oligoadenylate synthetase-like protein, and plasminogen activator inhibitor type 2. Other components of the plasminogen activator system were not induced. Plasminogen activator inhibitor type 2 is a down-regulator of the proteolytic cascade consisting of various metalloproteinases, some of which are induced by a carboxy-terminal Raf mutant (RafCT). In conclusion, RafCT induces factors which act in a conflicting manner in respect of carcinogenesis, especially within the proteolytic system of the extracellular matrix.
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PMID:Induction of putative tumor-suppressing genes in Rat-1 fibroblasts by oncogenic Raf-1 as evidenced by robot-assisted complex hybridization. 1104 81

Although the cyclooxygenase-2 (COX-2) pathway of the arachidonic acid cascade has been suggested to play an important role in colon carcinogenesis, there is little information concerning the identity of phospholipase A(2) (PLA(2)) involved in the arachidonic acid release in colon tumors. Here, we compared the potencies of three types of secretory PLA(2)s (group IB, IIA and X sPLA(2)s) for the arachidonic acid release from cultured human colon adenocarcinoma cells, and found that group X sPLA(2) has the most powerful potency in the release of arachidonic acid leading to COX-2-dependent prostaglandin E(2) (PGE(2)) formation. Furthermore, immunohistological analysis revealed the elevated expression of group X sPLA(2) in human colon adenocarcinoma neoplastic cells in concert with augmented expression of COX-2. These findings suggest a critical role of group X sPLA(2) in the PGE(2) biosynthesis during colon tumorigenesis.
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PMID:Potential role of group X secretory phospholipase A(2) in cyclooxygenase-2-dependent PGE(2) formation during colon tumorigenesis. 1115 May 21

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Molecular genetic analyses have clarified that accumulation of genome changes provides important steps in carcinogenesis. Urokinase type plasminogen activator (uPA) forms part of an important enzymatic system that degraded the extracellular matrix in process of invasion and metastasis. In order to study the kinetics of uPA cellular expression during this process, we used specific polyclonal antibodies against uPA in an immunohistochemistry assay in liver sections from a HCC in rats. The neoplastic transformation induced with this model was preceded by the appearance of numerous hyperplastic nodules during early stages, after time lesions progressed to well-differentiated HCC. The morphological changes of premalignant and malignant lesions were associated with a progressive increment of uPA expression, which reached its peak at 5 and 6 months after the administration of the carcinogenic drugs. Of the enzymatic markers analyzed, the gamma glutamyl transpeptidase showed correlationship with the histological findings. Our results suggest that the increase in the uPA expression should not only be considered as the hallmark of metastasis, but may also be related to early events in the neoplastic transformation and with the proliferation of vessels and biliary ducts.
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PMID:Expression of urokinase-type plasminogen activator in an experimental model of hepatocarcinoma. 1129 52

To elucidate the role of matrix metalloproteinases (MMP) in carcinogenesis, the expression of collagenases of types I (MMP-I) and IV (MMP-2 and MMP-9) as well as the behaviour of urokinase-like plasminogen activator (uPA) and of tissue MMP inhibitors (TIMP) in immortalized (IF) and transformed (TF) fibroblasts were investigated. The study was carried out using embryo rat fibroblasts, sequentially immortalized with the LT gene of human papilloma virus and transformed with the E7 gene of human papilloma virus (HPV-16). As control was used the primary fibroblast (PF) culture of Fisher rats. In IF, the collagenase activity was at the same level as it was in PF. The activity of uPA in IF was increased by 2-2.5-fold; the titrated amount of free endogenous inhibitors in IF and PF was at essentially the same level while being markedly higher than in TF. At the stage of fibroblast transformation with the E7 gene of HPV-16, there was seen an increase of Type IV collagenases and a decrease of Type I collagenase, both these indices being most pronounced in the cells with most developed tumorigenic properties. In TF there occurred a decrease of free endogenous MMP inhibitors relative to the enzyme activity and, at the same time, a decrease in uAF activity, indicating the changes occurring in the enzyme/inhibitor/activator ratio and hence the enhancement of the destructive potential of the cells (in this case, at the cost of Type IV collagenase activity).
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PMID:[Type I and IV collagenases and their endogenous regulators in immortalized and transformed fibroblasts]. 1138


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