Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Androgen (R1881) induced transcriptional activity of the human androgen receptor, stably expressed in CHO cells, can be stimulated an extra 2-fold by the addition of the protein kinase C activator, 4 beta-phorbol 12-myristate 13-acetate (PMA). This extra stimulation is not observed when the protein kinase A activator bromoadenosine 3':5'-cyclic monophosphate (8-BrcAMP) is used. The transcriptional activity was measured using a reporter plasmid containing the MMTV-promoter, coupled to the luciferase gene. The effect of PMA on R1881-induced transcription was not due to a higher expression level of the androgen receptor. Also, no extra phosphorylation of the androgen receptor could be measured after incubation with PMA. When GRE-tk-LUC and PSA-LUC reporters were used, the synergistic effect of PMA could not be observed. The findings on the composite MMTV-LTR promoter can be explained by either a direct synergistic interaction between occupied AP-1 like responsive elements and the androgen receptor or via an unknown transcription factor activated by the PKC pathway and interacting with the androgen receptor.
Mol Cell Endocrinol 1995 Apr 28
PMID:Synergism between androgens and protein kinase-C on androgen-regulated gene expression. 767 38

Antibodies raised against a Leishmania major recombinant promastigote surface antigen 2 (PSA-2) fragment recognized three major polypeptides of approximate M(r) 96,000, 80,000 and 50,000 in promastigotes of three Israeli isolates of L. major including the cloned line LRC-L137-V121, but detected a different array of polypeptides in other L. major isolates. The pattern was different both in number of polypeptides detected and their molecular weight. The antibodies to L. major PSA-2 also recognized polypeptides in L. tropica, L. donovani and very weakly in L. mexicana promastigotes and in Crithidia lucilliae. The number and size of the polypeptides was different in each species. In addition to the membrane-bound PSA-2 polypeptides we identified water-soluble forms of PSA-2 released in promastigote culture supernatants. Peptide maps of the various L. major PSA-2 membrane polypeptides showed they were different from each other. N-terminal amino acid sequence of the three polypeptides expressed by L. major showed they are similar but distinct, consistent with being members of a polymorphic family. Because of the extensive sequence similarity between the PSA-2 genes it has been difficult to assign protein products to individual genes. As a first step towards solving this problem, we have transfected into L. mexicana a genomic clone of a L. major PSA-2 gene and shown that it produces a M(r) 35,000 polypeptide recognized by monoclonal and polyclonal antibodies to L. major PSA-2.
Mol Biochem Parasitol 1994 Sep
PMID:Characterization of a polymorphic family of integral membrane proteins in promastigotes of different Leishmania species. 783 70

The objective of this prospective study was to evaluate the specificity of human sperm/zona pellucida interaction under hemizona assay (HZA) conditions in experiments with gametes from the same and different species. Human, cynomolgus monkey and hamster oocytes were used after salt-storage. Oocytes were bisected into matching hemizonae by micromanipulation and used in the HZA. Semen was obtained from healthy men (donors) and male cynomolgus monkeys and prepared by wash and swim-up. Sperm binding to matching hemizonae was assessed (tight binding) after 4-h coincubation in the HZA in homologous and interspecies experiments. Acrosome reaction was evaluated in the sperm droplets using FITC-PSA and on the hemizonae using the T-6 monoclonal antibody. On human hemizonae, the number of tightly bound sperm for human and monkey were 93.2 +/- 15.8 and 3.9 +/- 1.3, respectively (P < 0.001). On monkey hemizonae, the number of tightly bound sperm for monkey and human were 126.0 +/- 34.8 and 2.8 +/- 1.6, (P = 0.02) respectively. On hamster hemizonae, there was negligible binding of human and monkey sperm. There was a significantly higher incidence of acrosome reacted sperm on the zona pellucida in homologous compared to heterologous experiments. These results demonstrate a high species-specificity of human gamete functions under HZA conditions, providing further support for the use of this bioassay in infertility and contraception testing.
Mol Reprod Dev 1993 May
PMID:The specificity of human spermatozoa/zona pellucida interaction under hemizona assay conditions. 850 81

Metastatic prostate adenocarcinoma is a leading cause of cancer-related deaths among men. First line treatment is primarily aimed at blocking the synthesis and action of androgens. As primary endocrine treatment, androgen deprivation is usually achieved by orchidectomy or LHRH analogues, frequently combined with androgen receptor antagonists in order to block the residual adrenal androgens. However, nearly all the patients will eventually relapse. Available or potential second line therapies include, among others, alternative endocrine manipulations and chemotherapy. Cytochrome P450-dependent enzymes are involved in the synthesis and/or degradation of many endogenous compounds, such as steroids and retinoic acid. Some of these enzymes represent suitable targets for the treatment of prostate cancer. In first line therapy, inhibitors of the P450-dependent 17,20-lyase may achieve a maximal androgen ablation with a single drug treatment. Ketoconazole at high dose blocks both testicular and adrenal androgen biosynthesis but its side-effects, mainly gastric discomfort, limit its widespread use. A series of newly synthesized, more selective, steroidal 17,20-lyase inhibitors related to 17-(3-pyridyl)androsta-5,16-dien-3beta-ol, may open new perspectives in this field. In prostate cancer patients who relapse after surgical or medical castration, therapies aiming at suppressing the remaining adrenal androgen biosynthesis (ketoconazole) or producing a medical adrenalectomy (aminoglutethimide+hydrocortisone) have been used, but are becoming obsolete with the generalization of maximal androgen blockade in first line treatment. The role of inhibition of aromatase in prostate cancer therapy, which was postulated for aminoglutethimide, could not be confirmed by the use of more selective aromatase inhibitors, such as formestane. An alternative approach is represented by liarozole fumarate (LIA), a compound that blocks the P450-dependent catabolism of retinoic acid (RA). In vitro, it enhances the antiproliferative and differentiation effects of RA in cell lines that express RA metabolism, such as F9 teratocarcinoma and MCF-7 breast carcinoma cells. In vivo, monotherapy with LIA increases RA plasma levels and, to a greater extent, endogenous tissue RA levels leading to retinoid-mimetic effects. In the rat Dunning prostate cancer models, it inhibits the growth of androgen-independent as well as androgen-dependent carcinomas relapsing after castration. Concurrently, changes in the pattern of cytokeratins characteristic of increased differentiation were observed. Early clinical trials show that LIA, in second or third line therapy in metastatic prostate cancer, induces PSA responses in about 30% of unselected patients. In some patients regression of soft tissue metastasis ha been observed. In a subgroup of patients, an important relief of metastatic bone pain was also noted.
J Steroid Biochem Mol Biol 1996 Jan
PMID:P450-dependent enzymes as targets for prostate cancer therapy. 860 34

The promastigote surface antigen 2 (PSA-2) complex comprises a family of antigenically similar polypeptides of M(r) 96,000, 80,000 and 50,000, anchored to the membrane with glycosylphosphatidylinositol. Although PSA-2 was initially detected only in promastigotes, Northern blot analysis indicated that mRNA transcripts are also present in amastigotes. Unlike the situation in promastigotes, where at least four major transcripts (2.6-5.3 kb) were detected, only one major (2.6 kb) and two minor transcripts were present in amastigotes. A cDNA clone encoding a member of the PSA-2 family expressed in amastigotes was isolated using DNA probes. The predicted protein sequence of M(r) 40,000 is distinct from promastigote sequences, but shows significant similarity to previously described members of the family from L major and L amazonensis. Antibodies to the carboxyl terminal sequence conserved in all L major PSA-2 studied to date, as well as antibodies affinity purified on the amastigote cDNA-derived polypeptide recognized a major M(r) 50,000 amastigote polypeptide. Immuno-electron microscopy localized both promastigote and amastigote PSA-2 to the cell surface. The expression of PSA-2 polypeptides during the transformation of amastigotes into promastigotes was ordered in a time-dependent manner, with the promastigote M(r) 80000 polypeptide appearing first, followed by the M(r) 96000 polypeptide. In contrast to the glycosylphosphatidylinositol anchor of promastigote PSA-2, which could be hydrolysed by phosphatidylinositol-specific phospholipase C, the amastigote form was resistant to this enzyme.
Mol Biochem Parasitol 1995 Nov
PMID:The Leishmania promastigote surface antigen 2 complex is differentially expressed during the parasite life cycle. 871 60

The hypothesis of a neurodevelopmental dysfunction being involved in the etiology of schizophrenia is suggested by the observation of morphological alterations in the brains of schizophrenia patients. These alterations may be caused by defects in neural cell differentiation or migration, which could lead to disrupted neuronal circuitry and to the schizophrenia symptomatology. The neural cell adhesion molecule (NCAM) plays a major role in cell migration and axon outgrowth, and is involved in synaptic plasticity mechanisms implicated in adult cognitive functions. Altered levels of the NCAM polysialylated form, PSA-NCAM, in the brain of schizophrenia patients have been reported, and are supportive of a role for this molecule in the disorder. To investigate the possible involvement of the NCAM gene in schizophrenia, we conducted a comprehensive genetic study, which included linkage analysis and an association study employing the Haplotype Relative Risk (HRR) design in nuclear families. Our results indicate that structural alterations in the NCAM gene are unlikely to play a major role in schizophrenia, although a function for the NCAM molecule in the etiology of the disease remains an intriguing hypothesis.
Mol Psychiatry 1997 Jan
PMID:NCAM and schizophrenia: genetic studies. 915 19

As part of the study on the potential use of natural product-based combination therapy for treating prostate cancer, we have investigated the effects of a "HPLC standardized" herbal preparation, PC-SPES, on the prostate LNCaP cell line. Proliferation of the LNCaP cells was inhibited by a 4-6 day incubation with ethanolic extracts of PC-SPES. Decrease of cell growth was accompanied by a 60-70% down-regulation of the proliferating cell nuclear antigen (PCNA) and level of secreted PSA. A smaller and more variable decrease (20-40%) in the level of intracellular PSA was also observed. The PC-SPES-modulated PSA changes occurred concurrently with the decrease of AR expression, based on Western blot analysis and binding to the radioactive ligand [3H]R1881. A 60% decrease in R1881 binding occurred after a 24 h incubation with PC-SPES. These results suggest that PC-SPES negatively affects cell growth in part through its ability to modulate changes in PCNA, and may decrease PSA levels indirectly by suppressing AR expression.
Biochem Mol Biol Int 1997 Jul
PMID:Regulation of androgen receptor (AR) and prostate specific antigen (PSA) expression in the androgen-responsive human prostate LNCaP cells by ethanolic extracts of the Chinese herbal preparation, PC-SPES. 924 11

1. The adult hypothalamoneurohypophysial system (HNS) undergoes reversible morphological changes in response to physiological stimulation. 2. In the hypothalamus, stimulation of neurohormone secretion results in reduced astrocytic coverage of oxytocinergic somata and dendrites so that their surfaces become directly juxtaposed. Concurrently, there is a significant increase in the number of GABAergic, glutamatergic. and noradrenergic synapses impinging on the neurons. 3. In the neurohypophysis, stimulation induces retraction of pituicyte processes from the perivascular area and enlargement and multiplication of neurosecretory terminals. 4. These neuronal-glial and synaptic changes are reversible with cessation of stimulation, thus rendering the HNS an excellent model to study physiologically linked structural neuronal plasticity in the adult CNS. 5. We still do not know the cellular mechanisms and factors underlying such plasticity. Recent studies indicate, however, that the adult HNS expresses molecular characteristics normally associated with histogenesis and/or tissue reorganization in developing or regenerating neural systems. They include expression of cell adhesion molecules such as the highly sialylated isoform of the neural cell adhesion molecule, PSA-NCAM, and the glycoproteins, F3 and tenascin-C. 6. The expression of PSA-NCAM and tenascin-C does not show striking differences in terms of age, sex or physiological condition but that of F3 varies considerably with neurohypophysial stimulation. 7. We postulate that such molecular features allow magnocellular neurons and their glia to undergo neuronal-glial and synaptic plasticity throughout life, provided the proper stimulus intervenes. 8. Thus, in the hypothalamic nuclei, centrally released oxytocin acting in synergy with steroids can induce such plasticity, while adrenaline, acting through beta-adrenergic mechanisms, does so in the neurohypophysis.
Cell Mol Neurobiol 1998 Apr
PMID:Factors governing activity-dependent structural plasticity of the hypothalamoneurohypophysial system. 953 94

In this study cytoskeletal antigens common to brushtail possum and tammar wallaby spermatozoa were characterised using a monoclonal antibody (PSA-10). Using indirect immunofluorescence, the PSA-10 antibody detected antigens predominantly associated with the midpiece and principal piece of mature, permeabilised marsupial spermatozoa. The principal piece determinant, shared by a variety of other species, was found to arise in the marsupial testis. Midpiece localisation of the PSA-10 epitope was detected only in marsupial spermatozoa and shown to arise in the epididymis. Immunogold labelling demonstrated that the PSA-10 antigens were predominantly associated with the fibrous sheath and midpiece fibre network of both possum and wallaby spermatozoa. Western blotting suggested that two major possum and wallaby sperm polypeptides of 158 and 182 kDa were associated with the midpiece fibre network, a cytoskeletal structure unique to marsupial spermatozoa. A 32 kDa polypeptide was associated with the principal piece fibre network and/or fibrous sheath. The finding that these marsupial sperm cytoskeletal proteins share a common linear epitope suggests that they share some sequence similarity. The midpiece fibre network of marsupial sperm, like the fibrous sheath, has been proposed to have a structural role in providing passive stiffening for the flagellum (Harding et al., 1975, 1979; Olsen, 1975). The PSA-10 monoclonal antibody may provide a tool for comparative studies of mammalian sperm cytoskeletal proteins, particularly the marsupial midpiece fibre network. It may also allow the formation of this unique marsupial cytoskeletal structure, and its fate during the fertilisation process, to be followed by immunological means.
Mol Reprod Dev 1998 Aug
PMID:Characterisation of fibrous sheath and midpiece fibre network polypeptides of marsupial spermatozoa with a monoclonal antibody. 966 30

The authors investigated acrosomal changes occurring in boar sperm that interact with the expanded cumulus matrix surrounding ovulated pig oocytes. Samples of washed boar sperm obtained from six donors were incubated for 4 hr under capacitating conditions and exposed either to solubilized zonae pellucidae (ZP) or solubilized expanded pig cumuli (SEC) obtained from IVM oocytes. Alternatively, hyaluronic acid, laminin, or fibronectin, components of the extracellular matrix (ECM) were added to capacitated sperm. Acrosomal integrity was evaluated 1 hr later by using FITC-PSA staining. Solubilized cumuli induced acrosome reaction (AR) in a dose-dependent manner with a saturating effect exerted at 2.5 SEC/50 microl. Both 500 nM fibronectin and 500 nM laminin stimulated acrosomal exocytosis, the latter being more effective and inducing saturating levels of AR. By contrast, hyaluronic acid did not affect acrosomal status. Preincubation with anti-laminin antibodies completely prevented the inducing activity of SEC without affecting the activity of solubilized ZP. Consistent with these data, the integrin VLA-6, a receptor with high affinity for laminin, was detected by immunoblotting on the plasma membrane of capacitated boar spermatozoa. In addition, its immunoneutralization, obtained with the preincubation of capacitated sperm with the antibody raised against the alpha chain of VLA-6 integrin, prevented AR upon exposure to laminin or SEC (10.7+/-3.2 and 10.2+/-1.0% respectively), while the samples retained their responsiveness to ZP (29.6+/-1.2%). The results demonstrate that the interaction between laminin, entrapped in the expanded cumuli, and specific integrins present on the sperm membrane can initiate AR, thus taking part in the process of sperm-egg recognition.
Mol Reprod Dev 1998 Dec
PMID:Expanded cumuli induce acrosome reaction in boar sperm. 982 Feb 4


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