Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We established an androgen-sensitive cell line (BR31-5) from a ras + myc-induced mouse prostate carcinoma and used this cell line together with a previously reported transplantable androgen-independent mouse prostate carcinoma to investigate patterns of expression for apoptosis-related genes in an androgen-deprived environment. Single cell suspensions derived from the BR31-5 cell line were inoculated into the flank of intact or castrated adult male C57BL/6 mice and tumors were harvested 12 days post-inoculation for Northern blotting. A transplantable androgen-independent prostate cancer was also inoculated into intact or castrated mice and tumors harvested 21 days later. Tumor volume analyses showed that BR31-5 carcinomas were androgen-sensitive. Northern blotting showed that mRNA levels for two apoptosis-related genes, transforming growth factor-beta 1 and c-myc, were significantly elevated to a similar extent in carcinomas grown in castrated hosts compared to intact hosts for both the androgen-sensitive BR31-5 and androgen-independent carcinomas. Levels of mRNA for tissue type plasminogen activator, shown previously to be elevated in androgen-independent carcinomas following growth in castrates, were also increased in BR31-5 carcinomas under similar androgen-deprived conditions but to a lesser extent. Interestingly, testosterone repressed prostate mRNA No. 2 levels shown previously to be similar in both the intact and castrated groups for androgen-independent carcinomas were significantly increased in the castrated group compared to the intact group for BR31-5 carcinomas. Therefore, specific patterns of expression for apoptosis-related genes may be able to discriminate androgen-sensitive and androgen-independent prostate cancer under androgen-deprived conditions.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Androgen sensitivity and gene expression in ras + myc-induced mouse prostate carcinomas. 152 69

Co-secretion of plasminogen activator inhibitor type 1 (PAI-1) and urokinase-type plasminogen activator was identified in short-term cultures of primary type II pneumocytes isolated from adult rats. After separation by sodium dodecyl sulfate (SDS)-PAGE and reverse fibrin autography (reverse FA) of serum-free conditioned medium (SFCM), cellular lysate, and extracellular matrix (ECM), the inhibitor was seen as a zone of spared lysis at an apparent molecular mass of 46 to 48 kD. The plasminogen activator (PA) activity could only be visualized when human instead of bovine fibrin was used in the indicator gel. It presented as a single band of lysis at an apparent molecular mass of 45 kD when tested by regular FA and was found adjacent to PAI-1 when examined by reverse FA. Immunoblot analysis of type II pneumocyte SFCM, cellular lysate, and ECM revealed two bands at 46 and 48 kD, consistent with the apparent molecular masses (Mr) reported for rat PAI-1 from HTC hepatoma cells. Type II pneumocyte PAI-1 formed SDS-resistant complexes with tissue-type and urokinase-type plasminogen activator and was found to be stable to acid, to short-term exposure to heat, and to the denaturants guanidine HCl and SDS, while being sensitive to treatment with alkali and urea. When levels of type II pneumocyte PAI-1 activity were monitored over time during short-term culture conditions, the level of PAI-1 in SFCM remained stable, whereas activity in the lysate accumulated and activity in the ECM declined.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Feb
PMID:Plasminogen activator inhibitor type 1 production by rat type II pneumocytes in culture. 154 Mar 77

A clonal mouse prostate carcinoma was established by the introduction of the ras and myc oncogenes via the recombinant retrovirus Zipras/myc 9 using a mouse prostate reconstitution model system. A single-cell suspension derived from an early passage ras+myc-induced carcinoma was inoculated into the flanks of intact or castrated adult male C57BL/6 mice, and tumors were harvested 3 wk postinoculation for northern and Southern blotting. Tumor volume analysis showed that this carcinoma was not dependent on testicular androgens for growth. Southern blot analysis of virus-cell DNA junction fragments revealed that tumor cell populations recovered from both intact and castrated mice were progeny of the same virus-infected cell. Northern blotting showed that mRNA levels for the four growth-related genes transforming growth factor-beta 1 (TGF-beta 1), transforming growth factor-beta 3 (TGF-beta 3), tissue-type plasminogen activator (tPA), and c-myc were significantly elevated in clonal mouse prostate carcinomas grown in castrated hosts. In contrast, androgen receptor mRNA levels were significantly reduced under the same conditions. The response of TGF-beta 1, tPA, and c-myc mRNA levels in the carcinomas grown in castrated hosts was similar to that shown previously in normal rat ventral prostate. However, unlike normal rat ventral prostate after castration, increased numbers of apoptotic cells were not seen in the castrated group relative to the intact group at the time of analysis, indicating that the altered gene expression was not associated with cell death. In addition, testosterone-repressed prostate mRNA number 2 levels, shown previously to be elevated after castration in normal rat ventral prostate, were not increased in the androgen-deprived clonal mouse prostate carcinomas. Therefore, this early passage clonal ras+myc-induced prostate carcinoma demonstrates unique patterns of expression for a set of growth-related genes in an androgen-deprived environment.
Mol Carcinog 1992
PMID:Alterations in mRNA levels for growth-related genes after transplantation into castrated hosts in oncogene-induced clonal mouse prostate carcinoma. 154 41

The type of plasminogen activator (PA) secreted by bovine embryos was identified. Day 12-14 embryos were collected from estrus-synchronized, superovulated, and naturally mated crossbred beef cows. Embryos were left intact (E) or microdissected into component embryonic discs (ED) and trophoblastic vesicles (TV). Intact embryos, ED, and TV were pre-cultured for 2 days in Minimum Essential Medium Alpha (MEM alpha) with 10% heat-inactivated fetal calf serum, washed in serum-free MEM alpha, and cultured individually for 5 days in 50 microliters microdrops of MEM alpha with 15 mg/ml bovine serum albumin. At 24 hr intervals, E, ED, and TV were observed for tissue morphology and transferred to fresh microdrops, and medium was recovered and frozen at -20 degrees C. At the end of culture, blastocoelic fluid (BF) and embryonic tissues were recovered and frozen at -20 degrees C. Plasminogen activator concentrations in medium, tissues, and BF were determined by using a caseinolytic assay. Antibodies to urokinase-type PA (anti-uPA) and tissue-type PA (anti-tPA), and the urokinase inhibitor, amiloride (AMR), were used to identify the type of PA produced by bovine embryonic tissues. Intact embryos and TV released more PA (P less than 0.05) than ED, and tissues exhibiting expanded blastocoels released less PA (P less than 0.05) than tissues with collapsed blastocoels. Blastocoelic fluid from TV exhibited more PA (P less than 0.05) activity than from ED. Treatment with anti-uPA decreased PA activity (P less than 0.05) in pooled medium and tissues from E compared to treatment with nonspecific immunoglobulins and anti-tPA.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Reprod Dev 1992 Jan
PMID:Bovine embryos produce a urokinase-type plasminogen activator. 156 22

The amino acid sequence of the first domain of tissue-type plasminogen activator (t-PA) includes eight residues that are highly conserved in the type 1 finger domains found in human fibronectin. A construct comprising 50 residues from this finger domain of t-PA has been expressed and its solution structure has been determined by two-dimensional nuclear magnetic resonance spectroscopy. A total of 782 experimental restraints consisting of 723 interproton distances derived from nuclear Overhauser effect measurements, 43 torsion angles, and 16 hydrogen bond restraints were used as the input for dynamical simulated annealing structure calculations. Twenty-eight structures were obtained that satisfied the experimental data with no single distance violation greater than 0.3 A. The average atomic root-mean-square distribution for the backbone atoms of the final structures was 0.41 (+/- 0.13) A for the well defined part of the structure (residues 4 to 47). The overall fold of the t-PA finger domain shows a striking similarity to that of the seventh type 1 repeat of human fibronectin with the side-chains of conserved residues lying in similar conformations. One significant difference between the two molecules is that hydrophobic residues cover the exposed surface of the principal beta-sheet region in the t-PA finger domain. It is suggested that one face of this region may interact with parts of the complete t-PA protein.
J Mol Biol 1992 Jun 05
PMID:Solution structure of the fibrin binding finger domain of tissue-type plasminogen activator determined by 1H nuclear magnetic resonance. 160 84

Epidermal growth factor (EGF) induces tissue-type plasminogen activator (t-PA) biosynthesis in HeLa cells. Based on nuclear run-on transcription assays, t-PA biosynthesis is modulated by EGF on the level of gene transcription. The effect of EGF is slow, requiring 4-8 h to induce t-PA gene transcription and up to 24 h to induce t-PA mRNA and antigen secretion. An additive response is observed when cells are treated with both phorbol 12-myristate 13-acetate and EGF, suggesting that the two pathways converge and act independently to implement their respective effects. cAMP has previously been shown to potentiate phorbol 12-myristate 13-acetate-mediated induction of t-PA biosynthesis in HeLa cells and in human endothelial cells. Akin to this observation, cAMP also potentiates the EGF-mediated increase in t-PA mRNA. Maximal levels of t-PA mRNA is seen in the presence of all three agonists. The regulation of t-PA by EGF alone and in the presence of either PMA or cAMP is consistent with a role of t-PA during growth and development, and further indicates a functional interplay between protein kinase C-, tyrosine kinase, - and cAMP-dependent signal transduction pathways during regulation of t-PA gene expression.
Mol Endocrinol 1991 Dec
PMID:Regulation of human tissue-type plasminogen activator gene transcription by epidermal growth factor and 3',5'-cyclic adenosine monophosphate. 166 1

We have studied the effect of the adenylate cyclase-stimulating agent forskolin on expression of components of the plasminogen activation system in the human fibrosarcoma cell line HT-1080. By enzyme-linked immunosorbent assays, forskolin was found to cause a 2 to 4-fold decrease in intracellular and culture medium levels of type-1 inhibitor of plasminogen activators (PAI-1) and tissue-type plasminogen activator (t-PA). This was true for cells not treated with other agents and for cells, in which the PAI-1 and t-PA levels had been increased 5 to 10-fold by treatment with dexamethasone. This down-regulation could be traced back to corresponding decreases in the cellular levels of PAI-1 and t-PA mRNAs. Of the two PAI-1 mRNAs, the 2.4 kb species was 5-fold decreased by forskolin in cells treated with dexamethasone, while the 3.4 kb transcript was unaffected; in cells not treated with dexamethasone, forskolin affected the two PAI-1 transcripts in parallel. These studies show that in addition to the many inducers of PAI-1, PAI-1 gene expression is also subject to negative modulation by cyclic AMP. They also show that t-PA gene expression, in contrast to the induction by cyclic AMP observed in many other cell lines, may also be subject to negative regulation by cyclic AMP. Thus, hormonal agents acting with cyclic AMP as a second messenger may be involved in down-regulating PAI-1 and t-PA expression in vivo.
Mol Cell Endocrinol 1990 Aug 20
PMID:Forskolin down-regulates type-1 plasminogen activator inhibitor and tissue-type plasminogen activator and their mRNAs in human fibrosarcoma cells. 170 20

We have reported previously that incubation of HTC rat hepatoma cells with the synthetic glucocorticoid dexamethasone causes a 90% decrease in tissue-type plasminogen activator (tPA) activity secondary to a 4-fold increase in plasminogen activator inhibitor-1 (PAI-1) mRNA accumulation. Dexamethasone also induces a modest and transient increase in tPA mRNA. The cyclic nucleotide analog 8-bromo-cAMP (cA) causes a greater than 50-fold increase in PA activity, the result of a 90% decrease in PAI-1 and a sustained 2-fold increase in tPA mRNA accumulation. Dexamethasone and cA in combination cause a 150-fold increase in PA activity, the result of an 80% decrease in PAI-1 and a synergistic 15-fold increase in tPA mRNA. To determine the mechanism of this complex hormonal regulation, we have examined rates of synthesis and decay of PAI-1 and tPA mRNAs. Here we report that dexamethasone induces a 5-fold increase in PAI-1 gene transcription and does not significantly alter PAI-1 message decay; PAI-1 mRNA has a half-life of about 4 h in both untreated and dexamethasone-treated cells. In contrast, cA regulates PAI-1 mRNA by both decreasing the rate of PAI-1 gene transcription by 60% and accelerating the rate of PAI-1 message decay. Regulation of tPA by cA, both alone and in combination with dexamethasone, occurs primarily at the level of transcription. Dexamethasone and cA-induced tPA mRNA has a half-life of 2.75 h; tPA mRNA degradation is significantly inhibited by either cycloheximide or actinomycin-D.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1992 Jan
PMID:Transcriptional and posttranscriptional regulation of type 1 plasminogen activator inhibitor and tissue-type plasminogen activator gene expression in HTC rat hepatoma cells by glucocorticoids and cyclic nucleotides. 173 71

The solution structure of a recombinant tissue-type plasminogen activator kringle 2 domain, complexed with the antifibrinolytic drug 6-aminohexanoic acid (6-AHA) was determined via 1H nuclear magnetic resonance spectroscopy and dynamical simulated annealing calculations. The structure determination is based on 610 intramolecular kringle 2 and 14 intermolecular kringle 2-6-AHA interproton distance restraints, as well as on 82 torsion angle restraints. Three sets of simulated annealing structures were computed from three different classes of starting structures: (1) random conformations devoid of disulfide bridges; (2) random conformations that contain correct disulfide bonds; and (3) a folded conformation modeled after the homologous prothrombin kringle 1 X-ray crystallographic structure. All three sets of structures are well defined, with averaged atomic root-mean-square deviations between individual structures and mean set structures of 0.77, 0.99 and 0.70 A for backbone atoms, and 1.36, 1.55 and 1.41 A for all atoms, respectively. Kringle 2 is an oblate ellipsoid with overall dimensions of approximately 34 A x 30 A x 17 A. It exhibits a compact globular conformation characterized by a number of turns and loop elements as well as by one right-handed alpha-helix and five (1 extended and 4 rudimentary) antiparallel beta-sheets. The extended beta-sheet exhibits a right-handed twist. Close van der Waals' contacts between the Cys22-Cys63 and Cys51-Cys75 disulfide bridges and the central hydrophobic core composed of the Trp25, Leu46, His48a and Trp62 side-chains are among the distinguishing features of the kringle 2 fold. The binding site for 6-AHA appears as a rather exposed cleft with a negatively charged locus defined by the Asp55 and Asp57 side-chains, and with an aromatic pocket structured by the Tyr36, Trp62, His64 and Trp72 side-chains. The Trp62 and His64 rings line the back surface of the pocket, while the Tyr36 and Trp72 rings confine it from two sides. The Trp62 and Trp72 indole rings conform a V-shaped groove. The methyl groups of Val35 also contribute lipophilic character to the ligand-interacting surface. It is suggested that the positively charged side-chains of Lys34 and, potentially, Arg69 may favor interactions with the carboxylate group of the ligand. The Trp25 and Tyr74 aromatic rings, although conserved elements of the binding site structure, seem not to undergo direct contacts with the ligand.
J Mol Biol 1991 Dec 20
PMID:Solution structure of the tissue-type plasminogen activator kringle 2 domain complexed to 6-aminohexanoic acid an antifibrinolytic drug. 176 44

The data reviewed above show that the ideal thrombolytic or thrombolytic plus anticoagulant regimen does not exist. Nor is it clear to me that one regimen is unequivocally better than another in regards to clinical outcome. Publication of the full results of the ISIS-3 study and completion of the TAPS study, the GUSTO study, the TIMI-4 study plus others only now in the planning phases, should help. This review will not stay current very long. These data do, however, give some guides to certain circumstances in which one regimen might be preferred over others. If economics is a compelling issue, as it may be in public hospitals on a fixed budget or in the developing world, streptokinase may be the best choice. For early application of thrombolytic therapy, such as at the site of infarct occurrence and in automotive and aerial ambulances, anistreplase may be preferred because of its ease of administration. Previous administration of streptokinase or anistreplase (within the period of 48 h to 6 months after prior use) militate against their use as does a recent streptococcal infection. Heightened concerns about bleeding risk, except intracranially, in the absence of absolute contraindication of fibrinolytic therapy, e.g. remote gastrointestinal hemorrhage or the expected imminent need for an invasive procedure, may lead to preference for alteplase over streptokinase or anistreplase. On the other hand, heightened concerns about intracranial hemorrhage may lead to preference for streptokinase over alteplase or anistreplase. Alteplase may be preferred over non-fibrin-selective agents in the treatment of patients when administration is begun more than three hours after the presumed onset of infarction. These considerations notwithstanding, it is crucial that debates over the best choice of a regimen must not be allowed to prolong the time before administration of an effective thrombolytic agent to a patient with evolving Q-wave infarction who is a good candidate for this therapy. This review may also become dated in the not-too-distant future because of expected further advances in thrombolytic regimen. Application of new antithrombotic regimens was noted above. Future thrombolytic and antithrombotic regimens may be "cocktails" of one or more thrombolytic agents plus more powerful antithrombotic and antiplatelet agents. New generations of thrombolytic agents may replace the current first and second generation agents now used. Combination thrombolytic and anti-fibrin antibody agents and mutant tissue-type plasminogen activators with lower affinity for plasminogen activator inhibitor and longer half-lives are being developed.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Biol Med 1991 Apr
PMID:Considerations affecting selection of thrombolytic agents. 180 63


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