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At least 127 records · Page 7Linked to original sources
PubMed1981

Reduction of prostatic binding protein-messenger ribonucleic acid sequences in rat prostate by castration.

Messenger RNA coding for the three subunits of prostatic binding protein was isolated from polysomal RNA of rat ventral prostate by oligo (dT)-cellulose affinity chromatography and purified by repeated sedimentations through sucrose gradients under denaturing conditions. The purified mRNA migrated as a 9S peak in sucrose gradient centrifugation and hybridized with its cDNA within 2 log Rot units. In a cell-free reticulocyte lysate system, the mRNA directed the synthesis of three polypeptides of 12000, 9000, and 8000 daltons. These translation products were identified as the subunits of prostatic binding protein by immunoreaction with antibodies to this protein. Quantitation of prostatic binding protein-mRNA sequences in normal and castrated rats by hybridization with the cDNA probe showed that 3-day castration reduced the prostatic binding protein-mRNA sequences to less than 2% of the normal level. Similar hybridization was performed by using the cDNA to determine the level of prostatic binding protein coding sequences in polysomal poly(A) RNA following castration. The results showed a first-order rate constant of 3.92 X 10-2 h-1 for reduction of prostatic binding protein-mRNA sequences in polysomes. The period of castration required to reduce the level of these sequences to 50% of the normal level was calculated to be 17.6 h.

Androgen-Binding Protein↗
PubMed1999

Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP.

Raf-1 phosphorylates and activates MEK-1, a kinase that activates the extracellular signal regulated kinases (ERK). This kinase cascade controls the proliferation and differentiation of different cell types. Here we describe a Raf-1-interacting protein, isolated using a yeast two-hybrid screen. This protein inhibits the phosphorylation and activation of MEK by Raf-1 and is designated RKIP (Raf kinase inhibitor protein). In vitro, RKIP binds to Raf-1, MEK and ERK, but not to Ras. RKIP co-immunoprecipitates with Raf-1 and MEK from cell lysates and colocalizes with Raf-1 when examined by confocal microscopy. RKIP is not a substrate for Raf-1 or MEK, but competitively disrupts the interaction between these kinases. RKIP overexpression interferes with the activation of MEK and ERK, induction of AP-1-dependent reporter genes and transformation elicited by an oncogenically activated Raf-1 kinase. Downregulation of endogenous RKIP by expression of antisense RNA or antibody microinjection induces the activation of MEK-, ERK- and AP-1-dependent transcription. RKIP represents a new class of protein-kinase-inhibitor protein that regulates the activity of the Raf/MEK/ERK module.

3T3 Cells↗
PubMed2003

Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2.

Feedback inhibition is a fundamental principle in signal transduction allowing rapid adaptation to different stimuli. In mammalian cells, the major feedback inhibitor for G-protein-coupled receptors (GPCR) is G-protein-coupled receptor kinase 2 (GRK-2), which phosphorylates activated receptors, uncouples them from G proteins and initiates their internalization. The functions of GRK-2 are indispensable and need to be tightly controlled. Dysregulation promotes disorders such as hypertension or heart failure. In our search for a control mechanism for this vital kinase, here we show that the Raf kinase inhibitor protein (RKIP) is a physiological inhibitor of GRK-2. After stimulation of GPCR, RKIP dissociates from its known target, Raf-1 (refs 6-8), to associate with GRK-2 and block its activity. This switch is triggered by protein kinase C (PKC)-dependent phosphorylation of the RKIP on serine 153. The data delineate a new principle in signal transduction: by activating PKC, the incoming receptor signal is enhanced both by removing an inhibitor from Raf-1 and by blocking receptor internalization. A physiological role for this mechanism is shown in cardiomyocytes in which the downregulation of RKIP restrains beta-adrenergic signalling and contractile activity.

Androgen-Binding Protein↗
PubMed1999

Heterotopic endochondrial ossification with mixed tumor formation in C3(1)/Tag transgenic mice is associated with elevated TGF-beta1 and BMP-2 expression.

Transgenic mice which express the simian virus 40 large T-antigen (Tag) under the regulatory control of the hormone responsive rat C3(1) gene develop unusual lesions of heterotopic bone growth associated with mixed tumor formation arising from eccrine sweat glands found only in the foot pads of mice, ischiocavernosus muscle adjacent to bulbourethral glands and occasionally the salivary and mammary glands. These lesions are very similar to mixed tumors arising in several types of human cancers. Based upon electron microscopic examination and immunocytochemical analyses of cellular differentiation markers, the mixed proliferative lesions in this transgenic mouse model begin with the Tag-induced proliferation of epithelial and myoepithelial cells. The proliferation of these two types of cells results in hyperplasia and adenomatous transformation of the epithelial component, whereas the proliferating myoepithelial cells undergo metaplasia to form chondrocytes which deposit extracellular matrix, including collagen fibers. Cartilage develops focally between areas of epithelial proliferation and subsequently ossifies through a process of endochondrial bone formation. The metaplasia of myoepithelial cells to chondrocytes appears to require the inductive interaction of factors produced by the closely associated proliferating epithelial cells, including members of the TGF-beta superfamily. We demonstrate that TGF-beta1 protein accumulates in the extracellular matrix of the lesions, whereas RNA in situ hybridization reveals that BMP-2, another strong inducer of heterotopic bone formation, is overexpressed by the proliferating epithelial cells during the development of ectopic bone. The formation of sarcomatous tumors within the mixed tumors appears to be androgen-dependent and more frequent in mice lacking a normal allele of p53. This process of cartilage and bone induction may mimic epithelial-mesenchymal interactions which occur during embryonic bone formation. These transgenic mice may provide new insights into the processes of ectopic endochondrial bone formation associated with mixed tumor formation and serve as a useful model for human heterotopic bone disease.

Actins↗
PubMed2000

The C3(1)/SV40 T-antigen transgenic mouse model of mammary cancer: ductal epithelial cell targeting with multistage progression to carcinoma.

The 5' flanking region of the C3(1) component of the rat prostate steroid binding protein (PSBP) has been used to successfully target the expression of the SV40 large T-antigen (Tag) to the epithelium of both the mammary and prostate glands resulting in models of mammary and prostate cancers which histologically resemble the human diseases. Atypia of the mammary ductal epithelium develops at about 8 weeks of age, progressing to mammary intraepithelial neoplasia (resembling human ductal carcinoma in situ [DCIS]) at about 12 weeks of age with the development of invasive carcinomas at about 16 weeks of age in 100% of female mice. The carcinomas share features to what has been classified in human breast cancer as infiltrating ductal carcinomas. All FVB/N female mice carrying the transgene develop mammary cancer with about a 15% incidence of lung metastases. Approximately 10% of older male mice develop anaplastic mammary carcinomas. Unlike many other transgenic models in which hormones and pregnancy are used to induce a mammary phenotype, C3(1)/Tag mice develop mammary tumors in the mammary epithelium of virgin animals without hormone supplementation or pregnancy. Although mammary tumor development appears hormone-responsive at early stages, invasive carcinomas are hormone-independent, which corresponds to the loss of estrogen receptor-alpha expression during tumor progression. Molecular and biologic factors related to mammary tumor progression can be studied in this model since lesions evolve over a predictable time course. Genomic alterations have been identified during tumor progression, including an amplification of the distal portion of chromosome 6 containing ki-ras and loss of heterozygosity (LOH) in other chromosomal regions. We have demonstrated that stage specific alterations in the expression of genes which are critical regulators of the cell cycle and apoptosis are functionally important in vivo. C3(1)/Tag mice appear useful for testing particular therapies since growth of the mammary tumors can be reduced using chemopreventive agents, cytokines, and an anti-angiogenesis agent.

Androgen-Binding Protein↗
PubMed1996

cDNA cloning and tissue-specific expression of the phosphatidylcholine transfer protein gene.

We have isolated a cDNA containing the complete coding sequence of bovine liver phosphatidylcholine transfer protein (PC-TP). The deduced amino acid sequence consists of 213 amino acid residues and is, except for a lysine instead of an arginine at position 167, identical to the sequence determined by Edman degradation [Akeroyd, Moonen, Westerman, Puyk and Wirtz (1981) Eur. J. Biochem. 114, 385-391]. A cDNA encoding amino acid residues 41-214 of mouse lung PC-TP was also isolated. The predicted amino acid sequence was 90% similar (81% identical) to the corresponding sequence of bovine liver PC-TP, demonstrating that PC-TP is conserved among mammalian species. By Southern blot analysis, evidence was obtained for the presence of a single bovine PC-TP-encoding gene. The expression of the PC-TP gene was determined during mouse embryonic development and in adult mouse tissues using an RNase protection assay. PC-TP RNA was present in embryos at all stages of development as early as the embryonic stem cell, suggesting a role for PC-TP in cell growth and differentiation. Towards the end of embryonic development, just before term, high levels of PC-TP RNA were found in the liver. This level was even higher 7 days post-term. In addition to adult liver, high levels of PC-TP RNA were also found in kidney and testis. The prominent presence of PC-TP in developing and adult liver is compatible with its proposed role in bile formation.

Amino Acid Sequence↗
PubMed1994

Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene.

A transgenic mouse model for prostate and mammary cancer has been developed in mice containing a recombinant gene expressing the simian virus 40 early-region transforming sequences under the regulatory control of the rat prostatic steroid binding protein [C3(1)] gene. Male transgenic mice develop prostatic hyperplasia in early life that progresses to adenoma or adenocarcinoma in most animals surviving to longer than 7 months of age. Prostate cancer metastases to lung have been observed. Female animals from the same founder lines generally develop mammary hyperplasia by 3 months of age with subsequent development of mammary adenocarcinoma by 6 months of age in 100% of the animals. The development of tumors correlates with the expression of the transgene as determined by Northern blot and immunohistochemical analyses. The results of these experiments demonstrate that the C3(1) regulatory region used in these experiments is useful for targeting expression to the prostate and mammary gland. To our knowledge, this experimental system is the first reported transgenic mouse model for prostate cancer. These transgenic animals offer the opportunity to study hormone response elements in vivo and the multistage progression from normal tissue to carcinoma in the prostate and mammary glands.

Adenocarcinoma↗
PubMed1995

Mutant rat phosphatidylinositol/phosphatidylcholine transfer proteins specifically defective in phosphatidylinositol transfer: implications for the regulation of phospholipid transfer activity.

The mammalian phosphatidylinositol/phosphatidylcholine transfer proteins (PI-TPs) catalyze exchange of phosphatidylinositol (PI) or phosphatidylcholine (PC) between membrane bilayers in vitro. We find that Ser-25, Thr-59, Pro-78, and Glu-248 make up a set of rat (r) PI-TP residues, substitution of which effected a dramatic reduction in the relative specific activity for PI transfer activity without significant effect on PC transfer activity. Thr-59 was of particular interest as it is a conserved residue in a highly conserved consensus protein kinase C phosphorylation motif in metazoan PI-TPs. Replacement of Thr-59 with Ser, Gln, Val, Ile, Asn, Asp, or Glu effectively abolished PI transfer capability but was essentially silent with respect to PC transfer activity. These findings identify rPI-TP residues that likely cooperate to form a PI head-group binding/recognition site or that lie adjacent to such a site. Finally, the selective sensitivity of the PI transfer activity of rPI-TP to alteration of Thr-59 suggests a mechanism for in vivo regulation of rPI-TP activity.

Androgen-Binding Protein↗
PubMed2001

The phosphatidylethanolamine-binding protein is the prototype of a novel family of serine protease inhibitors.

Serine proteases are involved in many processes in the nervous system and specific inhibitors tightly control their proteolytic activity. Thrombin is thought to play a role in tissue development and homeostasis. To date, protease nexin-1 is the only known endogenous protease inhibitor that specifically interferes with thrombotic activity and is expressed in the brain. In this study, we report the detection of a novel thrombin inhibitory activity in the brain of protease nexin-1(-/-) mice. Purification and subsequent analysis by tandem mass spectrometry identified this protein as the phosphatidylethanolamine-binding protein (PEBP). We demonstrate that PEBP exerts inhibitory activity against several serine proteases including thrombin, neuropsin, and chymotrypsin, whereas trypsin, tissue type plasminogen activator, and elastase are not affected. Since PEBP does not share significant homology with other serine protease inhibitors, our results define it as the prototype of a novel class of serine protease inhibitors. PEBP immunoreactivity is found on the surface of Rat-1 fibroblast cells and although its sequence contains no secretion signal, PEBP-H(6) can be purified from the conditioned medium upon recombinant expression.

Amino Acid Sequence↗
PubMed1987

Involvement of the prostatic steroid-binding protein in the transfer of ligand to the dioxin receptor.

The prostatic steroid-binding protein (PSP) represents a highly abundant protein in the rat prostate which binds carcinogens reversibly and with high affinity. The biological role of PSP and the toxicological implications of the carcinogen-protein interaction are unclear. In this report, we have attempted to examine a possible role of PSP in the transfer of ligands to the dioxin receptor. PSP was purified from the rat ventral prostate and labeled in vitro with 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin (dioxin). Dioxin-labeled PSP was then incubated with rat liver cytosol in the presence or absence of a 200-fold excess of nonradioactive competitor, 2,3,7,8-tetrachlorodibenzofuran. After 2 h of incubation, a complete in vitro transfer of ligand from PSP to the rat hepatic dioxin receptor was observed, as assessed by velocity sedimentation analysis of specific dioxin binding. These results indicate that a high abundance carcinogen-binding protein, such as PSP, may be of importance in the cellular transfer of dioxin receptor ligands, thereby eliciting a receptor-mediated biochemical and/or toxic response.

Androgen-Binding Protein↗
PubMed1982

Prostatic steroid binding protein: organisation of C1 and C2 genes.

Prostatic steroid binding protein, whose expression is stimulated by androgens, consists of two subunits: one containing the polypeptides C1 and C3 and the other containing C2 and C3. We have characterised genomic clones containing the C1 and C2 genes by restriction enzyme analysis and DNA sequencing. Both genes are 3.2 Kb, have similar exon/intron arrangements and share considerable DNA sequence homologies in their coding regions, intervening sequences and 5' upstream DNA sequence which suggests that they have probably arisen from the duplication of an ancestral gene. The 5' termini of C1 and C2 mRNA have been mapped; the sequence TATAAA appears 30 nucleotides upstream but a CAAT-like sequence at -60 - -80 is absent. Finally, homologous human genes have not been detected.

Androgen-Binding Protein↗
PubMed1984

Rat prostatic steroid binding protein: characterisation of the Alu element upstream of the C3 genes.

We have characterised an Alu-like repetitive element found about 400 bp upstream of the gene encoding the C3 component of rat prostatic steroid binding protein and suggest, from comparisons with other published sequences, that it is an example of a third class of rodent Alu-equivalent sequences. Members of this class are 80-90 bp long, share greater than 90% sequence homology, and contain sequences resembling the RNA polymerase III bipartite promoter. The Alu type III element within the C3 gene was found to be expressed in cell-free systems and within heterologous cells stably transfected with the C3 gene, but these transcripts were not detectable in rat ventral prostate. It therefore seems unlikely that expression of this sequence plays a role in expression from the adjacent C3 gene.

Androgen-Binding Protein↗
PubMed1987

Rat prostatic binding protein: the complete sequence of the C2 gene and its flanking regions.

The complete sequence (2879 bp) of the androgen-controlled rat prostatic binding protein C2 gene and 1023 bp of the 5'- and 2127 bp of the 3'-flanking regions have been determined. The gene contains three exons (93, 203 and 147 bp) and two introns (1630 and 806 bp). It is flanked by two homopurine-homopyrimidine stretches of 55 and 131 nucleotides respectively, located at positions -405 and 4151. These sequences are remarkably sensitive towards S1-nuclease, indicating an altered DNA conformation under superhelical stress. Several palindromes and dyad structures are observed in the 5'-upstream region of the gene and at position -457, and 80% homology to the consensus sequence of a glucocorticoid receptor binding site is found.

Amino Acid Sequence↗
PubMed2003

The combined effects of vinclozolin and procymidone do not deviate from expected additivity in vitro and in vivo.

The combination effects of the well-known antiandrogenic fungicides, vinclozolin and procymidone, were tested both in vitro and in vivo. In vitro both vinclozolin and procymidone significantly inhibited the binding of agonist to the androgen receptor with the concentration that resulted in 50% inhibition (IC(50)) values of 0.1 and 0.6 micro M, respectively. By applying the isobole method, the effect of combining the two pesticides in vitro was found to be additive. In castrated testosterone-treated rats the administration of vinclozolin starting at 10 mg/kg led to a decrease in organ weight of all tested reproductive organs. The levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were increased significantly with doses of 100 mg/kg vinclozolin and above. Expression of the androgen-responsive gene, TRPM-2, was increased starting at 100 mg/kg vinclozolin. For procymidone, reproductive organ weights were diminished at 10 mg/kg and LH was increased at a concentration of 25 mg/kg and above, compared to the testosterone-treated controls. FSH was significantly increased only at 25 mg/kg procymidone. The studied gene expressions were changed by 100 mg/kg procymidone. Dosing the animals with a combination of a 1:1 mixture of vinclozolin and procymidone resulted in a weight reduction in the reproductive organs and an increase of serum LH and FSH as early as with 10 mg/kg combined dose. The relative expressions of TRPM-2 and PBP C3 were changed compared to controls at 100 mg/kg. The level of 5-HT in the rat brain was increased after a dose of 10 mg/kg. Using the isobole method, comparisons of the observed and predicted effects assuming additivity on reproductive organ weights, hormone levels, and gene expression showed agreement and thus the combination effects are suggested to be additive in vivo as well as in vitro.

Androgen Antagonists↗