Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glandular kallikrein (a trypsin-like serine protease) is an estrogen-induced and dopamine-repressed protein in the rat anterior pituitary which appears to be associated with lactotrophs. This study examined glandular kallikrein levels in diethylstilbestrol (DES)-induced pituitary tumors in F344 rats and compared it to plasma and pituitary prolactin, and pituitary wet weight. Ovariectomized F344 rats were implanted with Silastic tubes containing 0 or 5 mg DES for 1, 3, 5, 7, or 9 weeks. Glandular kallikrein was measured by microenzymatic assay using D-valylleucylarginyl-p-nitroanilide following trypsin treatment of extracts to activate latent forms of glandular kallikrein. Prolactin was measured by radioimmunoassay. DES induced steady time-dependent increases in pituitary wet weight with 7- and 16-fold increases observed by 5 and 9 weeks, respectively. Growth rates averaged 11.4 mg/week during the first 5 weeks of DES exposure, and then increased to 23.2 mg/week between weeks 5 and 9. Glandular kallikrein total activity (nmol/min/pituitary) increased 130- and 240-fold after 3 and 5 weeks of DES exposure, respectively, and then abruptly plateaued. The specific activity (nmol/min/mg protein) of glandular kallikrein peaked at 3-5 weeks (36-fold increase compared to controls) and then declined as pituitary protein but not glandular kallikrein continued to increase. Total pituitary prolactin constantly rose during DES exposure with 12- and 26-fold increases after 5 and 9 weeks, respectively. Plasma prolactin levels also continuously rose during exposure to DES with 130- and 290-fold increases after 5 and 9 weeks, respectively. No major strain differences were found with regard to sensitivity to the acute effects of estrogen or dopaminergic stimulation on glandular kallikrein induction. DES-induced pituitary tumors in F344 rats are well known to arise via lactotroph proliferation, and the striking elevation in glandular kallikrein and prolactin during the early phases of tumor growth provide further support for a localization of glandular kallikrein in lactotrophs. However, the abrupt stabilization in glandular kallikrein levels by week 5 was unexpected and may signal a biochemical transformation of the tissue during tumor progression.
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PMID:Glandular kallikrein in estrogen-induced pituitary tumors: time course of induction and correlation with prolactin. 339 Aug 8

A thiol proteinase inhibitor (TPI) has been purified from the ascitic fluid of Sarcoma 180 tumor-bearing mice. The molecular weight of the inhibitor was estimated to be 67,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the substance inhibited papain, cathepsins B and L, but not cathepsins H and D and trypsin. The inhibitor also liberated kinin upon treatment with trypsin or mouse glandular kallikrein, indicating that the inhibitor is a kininogen, and the kinin liberated upon trypsinization was identified as bradykinin. An immunoreactive TPI with a molecular weight indistinguishable from that of the ascites TPI was found in plasma of non-tumor-bearing mice as well as that of tumor bearers. Plasma levels of immunoreactivity were increased up to twice the normal levels in tumor bearers inoculated with Sarcoma 180 or 3LL tumor cells. Supplementation of the purified ascites TPI into Sarcoma 180 culture medium caused a significant suppression of cell growth as well as [3H]thymidine incorporation at a concentration below that normally present in plasma. In contrast, addition of ascites-TPI to cultured mouse embryonic cells caused enhancement of cell growth as well as [3H]thymidine incorporation. These results indicate that in mice responding to tumor growth, a TPI corresponding to a kininogen is induced which may regulate tumor growth by countering tumor-related proteolytic activity.
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PMID:Thiol proteinase inhibitor in the ascitic fluid of sarcoma 180 tumor-bearing mice. 366 64

Three distinct dissemination-related phenotypes have been distinguished among cell subpopulations of the mouse B16 melanoma: tumorigenicity, spontaneous metastasis from subcutaneous tumors, and organ colonization following intravenous injection of cells. From a progenitor clone (G3) of tumorigenic but nonmetastatic and noncolonizing (null) cells that underwent phenotypic diversification in vitro and in vivo, 4 subclones were obtained: G3.5 (culture-generated metastatic), G3.12 (tumor-generated metastatic), G3.15 (culture-generated null), and G3.26 (tumor-generated colonizing). The growth potentials of the parent clone and derived subclones were investigated comparatively in in vivo assays (tumorigenicity, tumor growth rate, and lung colonization potential), monolayer culture assays (generation time, saturation density, clonogenicity, and rate of detachment by trypsin), and in soft agar. In overall growth potential, G3.26 greater than G3.12 greater than G3, G3.5 greater than G3.15. These results indicate that metastatic populations of the B16 melanoma are not the most rapidly and effectively growing cells obtainable from that tumor.
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PMID:Growth characteristics of clonal cell populations constituting a B16 melanoma metastasis model system. 388 9

A cytolytic factor partially purified from eggs of the sea hare Aplysia kurodai was examined for cytolytic activity against various target cells. All kinds of tumor cells tested were lysed in vitro by the cytolytic factor in the range of 10-100 ng protein/ml. In contrast, normal spleen cells were lysed by 10 micrograms/ml of this factor and red cells were not lysed even at this higher concentration. Tumor lysis was time-dependent and was complete within 10 hr. This factor inhibited DNA and RNA syntheses of tumor cells but not protein synthesis. The cytolytic activity was lost on heat-treatment (60 degrees) and at pH 2, and was partially inhibited by treatment with 8M urea and at pH 12, but the factor was resistant to treatments with trypsin, periodate and 2-mercaptoethanol. Neutralizing activity was observed in vivo on pretreatment of MM46 and L1210 cells with the factor. This cytolytic factor also inhibited the growth of solid-type MH134 tumor and ascitic-type MM46 tumor. These results indicate that Aplysia eggs contain a novel cytolytic factor that lyses tumor cells in vitro and inhibits tumor growth in vivo.
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PMID:Cytolytic factor in eggs of the sea hare Aplysia kurodai. 653 65

A tumor-derived suppressor factor ( TDSF ) has been isolated from 3 M KCl extracts of a chemically induced fibrosarcoma of C3H/HeJ mice by preparative isoelectric focusing. Incubation of TDSF with normal spleen cells induces suppressor cells that enhance tumor growth and inhibit DTH to the chemical sensitizer 2,4-dinitro-1-chlorobenzene (DNCB). Similar suppressogenic activity has been detected in extracts of the 10T1/2 fibroblast line, an ultraviolet-induced fibrosarcoma of C3H/HeN mice, the C57B1/6J Lewis lung carcinoma, and four human colonic adenocarcinoma. TDSF activity was not found in extracts of syngeneic muscle or spleen cells. Chemical characterization of TDSF from the murine fibrosarcoma MCA-F revealed sensitivity to treatment with heat and RNase, partial sensitivity to treatment with trypsin, but resistance to treatment with DNase, pronase, and neuraminidase. TDSF has an apparent molecular weight of greater than 300 kDa by high-performance gel permeation chromatography. Acidic soluble factors isolated from murine and human tumors induce suppressor cells to inhibit cell-mediated immunity in an intact host.
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PMID:Soluble factors from murine and human tumors induce suppressor cells. 653 7

In previous studies, cultured melanoma cells were shown to have a suppressive influence on the induction of cytotoxic T cells. Our investigation of the mechanism of these effects revealed that supernatants from certain cultures of melanoma cells contained inhibitory activity against the production of interleukin 2 (IL 2) from phytohemagglutinin (PHA)-stimulated cultures of lymphocytes. These supernatants did not inhibit interleukin 1 production, and also did not inhibit the mitogenic activity of performed IL 2 on IL 2-dependent target cells. Production of the inhibitory activity could be reduced by inhibitors of protein synthesis, but this activity was not inhibited by digestion with the proteolytic enzymes trypsin or pronase. Gel filtration analysis of tumor supernatants revealed that the majority of the inhibitory activity was detected in fractions of approximately 44 and 7 Kd. The addition of supernatants with inhibitory activity to PHA-stimulated cultures of lymphocytes was associated with reduced transition of cells from G1 to S phase of cell division, which could be reversed by the addition of IL 2. Preliminary studies suggest that the release of the factor(s) from melanoma cells may be related to rapid progression of tumor growth in patients, and therefore may be of prognostic significance in tumor host relationships.
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PMID:Inhibition of interleukin 2 production by factors released from tumor cells. 660 93

An estrogen-responsive mouse Leydig cell tumor line (Tumor 124958) has been shown to contain only a low-affinity binder for estradiol in the cytosol fraction. This differed from the putative estrogen receptor in terms of its hormone-binding specificity as well as affinity. In addition, the possibility that an estrogen receptor-like molecule exists in the nuclei even without hormonal stimuli was examined using purified nuclei. Scatchard plot analyses showed that these nuclei possessed a large amount of estrogen binder having a high affinity for estradiol and diethylstilbestrol. The content of this nuclear binding component was not diminished by using molybdate, a potent inhibitor for receptor activation, and in vitro incubation of collagenase-dispersed cells with estradiol did not cause significant increase in the number of nuclear binding sites when compared with the values obtained by direct incubation of isolated nuclei with estradiol. These results support the view that this nuclear estrogen binder is not due to artificial migration of the cytosol receptor into nuclei during homogenization. The characterization of this nuclear binding component under cell-free conditions revealed that its affinity for estradiol in Mg2+-containing buffer was temperature dependent (Kd 3 nM at 30 degrees and 12 nM at 0 degrees) without significant alteration in the number of maximum binding sites. Introduction of a chelating agent (ethylenediaminetetraacetate) into the buffer system abolished the temperature effect on the affinity, resulting in high affinity for estradiol at both low and high temperatures. These Mg2+ and temperature effects were reversible. In addition, when compared with putative nuclear estrogen receptors, this nuclear binding was observed to be relatively resistant to high salt or micrococcal nuclease treatments in relation to solubilization from nuclei. However, trypsin digestion was found to result in a marked decrease in the nuclear binding sites, indicating that this unique nuclear binding component contains a protein unit(s). These results suggest the possibility that this tumor line contains a unique unoccupied nuclear estrogen binder which might be able to transmit estrogen signals to tumor cell nuclei with regard to tumor growth.
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PMID:Characterization of a unique nuclear estrogen-binding component in an estrogen-responsive mouse Leydig cell tumor. 687 50

Investigations were performed to elucidate changes in normal syngeneic recipients after they received tumor-sensitized cells. Transfer of regional or nonregional lymph node cells or spleen cells from tumor-bearing inbred C3HeB/FeJ mice to normal syngeneic recipients caused the recipients to produced bone marrow, which mediated in vitro cytolysis of immunizing tumor target cells. This finding was not entirely limited to transfer of lymphoid cells. The transfer of myeloid cells, granulocytes, and cultured macrophages from tumor-bearing mice also produced cytotoxic cells. The extent of cytotoxicity following cell transfer was related to the duration of tumor growth in cell donors, to the degree of cytotoxicity, and to the number of cells transferred. Both the iv and ip routes were equally effective. Treatment of cells before transfer with trypsin or pronase, mitomycin C, or sublethal irradiation failed to prevent development of cytotoxicity in cells of the recipient, whereas freeze-thawing abolished this event. Serum from the cell recipient could inhibit the cytotoxicity demonstrated by lymphoid cells derived from the recipient or from a tumor-bearing animal. The findings indicate that "information" transferred to normal animals not previously exposed to a tumor results in production of tumor-specific cytotoxic cells in these animals.
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PMID:Cellular cytotoxicity and serum inhibition in normal mice following transfer of syngeneic tumor-sensitized cells. 698 97

To understand how estradiol-17 beta (E2) influences MtTW15 rat pituitary tumor function, we have evaluated the cytosolic E2 binding properties of tumors derived from control and steroid treated host animals. Specific E2 binding (approximately 3 pmoles/g tumor) was observed in all groups and was steroid responsive. The E2 binding macromolecule migrated to 7S following sucrose density gradient sedimentation and was specific for estrogenic steroids. Saturation analysis of E2 binding revealed a high affinity interaction (Kd = 5.5 +/- 0.5 x 10(-10) M). Furthermore, E2 binding was temperature-sensitive and degraded by trypsin. Thus, the MtTW15 tumor contains an estrogen receptor. Accordingly, the effects of 4 antiestrogenic drugs on tumor estrogen-receptor levels, tumor growth and hormone production were evaluated. In general, these drugs reduced cytosolic estrogen receptor levels, promoted tumor growth and increased tumor growth-hormone production. It is suggested that these compounds can exert both estrogen agonist and antagonist properties in MtTW15 tumors.
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PMID:Estrogen receptor-like macromolecule in MtTW15 rat pituitary tumors: effects of antiestrogens. 728 85

3-Methylcholanthrene-induced tumor was challenged with a low molecular synthetic protease inhibitor, [N,N-dimethylcarbamoylmethyl 4-(4-guanidinobenzoyloxy)-phenylacetate] methanesulfate. This drug at a dosage of 10 mg/kg or 20 mg/kg was administered by ip injection to 20 mice each harboring a solitary tumor twice daily for 10 weeks. This protease inhibitor significantly inhibited tumor growth and prolonged the survival time of the tumor-bearing mice (P less than 0.001). The results suggest the involvement of kinin-forming proteases, such as trypsin, plasmin and kallikrein, in the tumor growth.
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PMID:Inhibition of growth of 3-methylcholanthrene-induced mouse skin tumor by protease inhibitor [N,N-dimethylcarbamoylmethyl 4-(4-guanidinobenzoyloxy)-phenylacetate] methanesulfate. 734 42


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