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)

A current hypothesis suggests that androgen administration prior to chemotherapy (androgen priming) may potentiate tumor cytotoxicity in prostate cancer. The Dunning R3327G rat prostatic tumor model was used to test this concept experimentally. Control groups without priming included (1) intact untreated, (2) castrate alone and (3) castrate+ chemotherapy (cyclophosphamide, 30 mg/kg/day for 2 days with repeat cycle in 25 days- CTX). Two experimental groups received androgens, one before and one after chemotherapy. Treatment effect was monitored by quantitating tumor volume and animal survival. Control groups receiving castration and chemotherapy had a retardation of tumor growth and a prolongation of survival when compared to untreated animals. Androgen priming before but not after chemotherapy enhanced the degree of tumor suppression. With the androgen-priming protocol, all androgen-primed tumors had regressed, 3/6 tumors had disappeared and 3 were only palpable. At the same time point, tumors in all the other groups were actively growing and had volumes greater than the initial values (P less than 0.01). Median survival was significantly prolonged in primed animals 191 vs 40 days for untreated animals and 150 days for the nonprimed castration + chemotherapy animals (P less than 0.02). These findings have been repeated with several replicate experiments. These observations confirm the hypothesis that androgen priming can potentiate chemotherapy in an experimental system.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Androgen-primed chemotherapy-experimental confirmation of efficacy. 228 85

The oestrogen receptor is a member of a supergene family that includes receptors for steroid and thyroid hormones, vitamin D3, and retinoic acid. A number of additional members of the family have been cloned where the putative ligand remains to be identified. The oestrogen receptor is a ligand-activated transcription factor that modulates specific gene expression by binding to short DNA sequences (oestrogen response elements) located in the vicinity of oestrogen-regulated genes. Regions of the receptor responsible for hormone-binding. DNA-binding and activation of transcription, have been identified. The anti-oestrogen, tamoxifen (Nolvadex), behaves as a weak oestrogen agonist. A model, based upon our current understanding of the molecular mechanism of oestrogen action, will be presented to explain the cell and gene specific effects of some anti-oestrogens.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Modulation of oestrogen receptor activity by oestrogens and anti-oestrogens. 228 86

The site-specific integration of the phage phi CTX genome, which carries the gene for a pore-forming cytotoxin, into the Pseudomonas aeruginosa chromosome was analysed. The 1,167 bp integrase gene, int, located immediately upstream of the attachment site, attP, was characterized using plasmid constructs, harbouring the integration functions, and serving as an integration probe in both P. aeruginosa and Escherichia coli. The attP plasmids p1000/p400 in the presence of the int plasmid pIBH and attP-int plasmids pINT/pINTS can be stably integrated into the P. aeruginosa chromosome. Successful recombination between the attP plasmid p1000 and the attB plasmid p5.1, in the presence of the int plasmid pIBH in E. coli HB101 showed that the int gene is active in trans in E. coli. The int gene product was detected as a 43 kDa protein in E. coli maxicells harbouring pINT. Proposed integration arm regions downstream of attP are not necessary for the integration process. pINT and phage phi CTX could be integrated together into P. aeruginosa chromosomal DNA, yielding double integrates.
Mol Gen Genet 1995 Jan 06
PMID:Site-specific integration of the phage phi CTX genome into the Pseudomonas aeruginosa chromosome: characterization of the functional integrase gene located close to and upstream of attP. 782 14

The peptide Ca2+ channel antagonists omega-conotoxin (omega-CTX) MVIIC and omega-grammotoxin (omega-GTX) SIA were studied by measuring their effects on the release of [3H]glutamate from rat brain synaptosomes. The pseudo-first-order association constant for omega-CTX MVIIC (1.1 x 10(4) M-1 sec-1) was small, relative to that for omega-GTX SIA (3.6 x 10(5) M-1 sec-1). Equilibrium experiments showed that omega-CTX MVIIC blocked approximately 70% of Ca(2+)-dependent glutamate release evoked by 30 mM KCl (IC50 approximately 200 nM), whereas omega-GTX SIA virtually eliminated release, with lower potency (IC50 approximately 700 nM). At stronger depolarizations (60 mM KCl), neither toxin (at 1 microM) showed significant block of release, but when these or other Ca2+ channel antagonists (omega-CTX GVIA or omega-agatoxin IVA) were used in combination a substantial fraction of release was blocked. [3H]Glutamate release that was resistant to omega-CTX MVIIC was characterized with respect to its sensitivity to block by omega-GTX SIA and the inorganic blocker Ni2+. Both omega-GTX SIA and Ni2+ were relatively weak blockers of the resistant release. These results suggest that a previously uncharacterized Ca2+ channel exists in nerve terminals and can be distinguished on the basis of its resistance to omega-CTX MVIIC and its weak sensitivity to omega-GTX SIA and Ni2+. Thus, at least three channel types (P, N, and a "resistant" type) contribute to excitation-secretion coupling in nerve terminals.
Mol Pharmacol 1995 Feb
PMID:Characterization of presynaptic calcium channels with omega-conotoxin MVIIC and omega-grammotoxin SIA: role for a resistant calcium channel type in neurosecretion. 787 43

The structure of cardiotoxin CTX I from Naja naja atra has been investigated by NMR spectroscopy. Sequence specific resonance assignments have been obtained for all backbone protons as well as for most side-chain protons. Distance geometry calculations were carried out using a metric matrix DG program. A total of 715 NOE constraints, 27 phi angle constraints and a list of the hydrogen bond donors were used for the metric matrix DG calculations and refinement. The average pairwise r.m.s.d. of the resulting structures was 1.01 A for the backbone heavy atoms, and 1.69 A for all heavy atoms. The protein is rich in beta structure and consists of a large triple-stranded, antiparallel beta sheet as well as a short double-stranded, antiparallel beta sheet. Non-regular hydrogen bonding is found between side-chains of the carboxy-terminal end and the rest of the core region. The structure is discussed in terms of evolutionary aspects as well as recent investigations about the biological function and active site.
J Mol Biol 1994 Jul 29
PMID:Structure of cobra cardiotoxin CTX I as derived from nuclear magnetic resonance spectroscopy and distance geometry calculations. 804 50

Cardiotoxin III (CTX III), a major cardiotoxin analogue isolated from the Taiwan cobra (Naja naja atra) venom was modified, either with trinitrobenzene sulfonate (TNBS) or 4-chloro-3,5-dinitrobenzoate (CDNB). Under the conditions of limited reagent availability, three mono-TNP derivatives modified at Lys-5, 12, or 44, and three mono-CDNP derivatives at Lys-12, 23, or 44 were isolated, respectively. The biological activities of CTX III were more or less affected after each of these reactive amino groups were modified. In particular, the hemolytic activity to human erythrocytes and cytotoxicity on NS-1 cells of CTX III decreased to 31% and 50%, respectively, when Lys-12 was trinitrophenylated. More pronounced alteration in these activities was observed as this amino group was carboxydinitrophenylated. A good correlation between the hemolytic activity and cytotoxicity was found. These results indicate that epsilon-amino group at Lys-12 is most closely related to the hemolytic and cytotoxic activities of CTX III. The antigenicity of modified derivatives still remained intact as measured by ELISA.
Biochem Mol Biol Int 1993 Sep
PMID:Chemical modification of amino groups in cardiotoxin III from Taiwan cobra Naja naja atra) venom. 826 Sep 41

The Pseudomonas aeruginosa ctx gene encoding cytotoxin is carried by a temperate phage phi CTX. The genome of phi CTX is a 35.5 kb double-stranded DNA with cohesive ends (cos). It is unique in that the ctx gene and attP site of phi CTX exist very close to the respective cohesive ends. In this study, we determined the structure of this attP-cos-ctx region. The termini of phi CTX are 21-base 5' extended-single-stranded DNAs. The ctx gene is located 361 bp downstream of the left end (cosL). The attP core sequence of 30 bp exists only 647 bp apart from the right end (cosR). The attP-cos-ctx region contains six kinds of repeats and integration host factor-binding sequences and showed sequence-directed static bends, suggesting its potential to form a highly ordered structure. In addition, phi CTX was found to integrate into the serine tRNA gene which was mapped to the 43-45 min region on the P. aeruginosa chromosome.
Mol Microbiol 1993 Mar
PMID:Molecular analysis of a cytotoxin-converting phage, phi CTX, of Pseudomonas aeruginosa: structure of the attP-cos-ctx region and integration into the serine tRNA gene. 846 12

Enhanced responsiveness of the pituitary gland to GnRH is a fundamental step required for secretion of the proestrous LH surge, and is achieved primarily by the actions of ovarian steroid hormones on the gonadotropes. The mechanisms involved are still unclear but the cAMP second messenger pathway can mediate some of these activities. The present study was undertaken to determine the effects of in vitro cholera toxin (CTX; increases cAMP) pretreatment of pituitary cells from proestrous and diestrous 1 rats relative to their LH secretory response to GnRH using a reverse hemolytic plaque assay. The number of gonadotropes that secrete LH in the group treated with CTX increased at low doses of GnRH and also in the absence of the peptide, but decreased at high doses, showing a dual effect: stimulation of some gonadotropes and inhibition of others. The inhibition was achieved within 3 h of pretreatment in proestrous cells but it was not seen until 20 h in diestrous 1 cells. This suggests the existence of at least two subpopulations of gonadotropes, one of which is stimulated by cAMP and another which is inhibited.
Mol Cell Endocrinol 1995 Oct 30
PMID:Effect of cAMP on GnRH stimulated LH secretion from individual pituitary gonadotropes. 867 37

GTP-binding proteins are key elements in coupling receptors to various effector systems. Using ADP-ribosylation by cholera (CTX) and pertussis (PTX) toxins and an immunodetection technique, we investigated the G protein expression profile in smooth muscle of stem villi vessels obtained from human term placentae. In placental vascular smooth muscle, we report the presence of two CTX-protein substrates of 42 and 45 kDa recognized by Gs alpha antibodies, and three Gi alpha isoforms, substrates of PTX, identified as Gi1 alpha, Gi3 alpha (two proteins of 41 kDa) and Gi2 alpha (a 40-kDa protein). We also characterized another target of PTX, a 40-kDa Go alpha-immunoreactive protein and detected the PTX-insensitive Gq-Gi1 alpha proteins. To assess the functional significance of the G alpha proteins identified in this tissue, we measured the adenylyl cyclase activity in the presence of guanyl nucleotides alone or with increasing concentrations of vasoactive intestinal peptide (VIP), and examined whether VIP-bound sites, in the presence of GTP gamma S, promote the release of G alpha proteins from the membranes of vascular smooth muscle. At low concentrations (0.1 nM to 0.01 microM), guanyl nucleotides stimulated adenylyl cyclase activity in a dose-dependent manner, while at higher concentrations (10 microM to 1 mM) the stimulation rate of cAMP production by guanyl nucleotides decreased. In a dose-dependent manner, VIP in the presence of GTP gamma S increased adenylyl cyclase activity and specifically promoted the release of both Gs alpha isoforms. In contrast, the release of Gi1 and Gi2 alpha isoforms was not significantly increased in the presence of VIP, while GTP gamma S alone stimulated their release. Our data show physical evidence of the activation of Gs proteins by VIP-bound membrane receptors, resulting in dissociation and release of Gs alpha subunits in the soluble fraction. They assess the specific coupling of the two Gi alpha isoforms to VIP receptors in smooth muscle wall of placental stem villi vessels. It would be of interest to investigate whether changes in Gs alpha expression and/or function are associated with the placental angiogenesis process during pregnancy.
J Mol Cell Cardiol 1996 May
PMID:G protein expression in human fetoplacental vascularization. Functional evidence for Gs alpha and Gi alpha subunits. 876 39

PiTX-K alpha, a 35-residue peptide recently isolated from the venom of Pandinus imperator, blocks the rapidly inactivating (A-type) K+ channel(s) in rat brain synaptosomes and the cloned Kv 1.2 potassium channel at very low toxin concentrations (6 nM and 32 pM, respectively) [Rogowski, R. S., Collins, J. H., O'Neil, T. J., Gustafson, T. A., Werkman, T. A., Rogawski, M. A., Tenenholz, T. C., Weber, D. J., & Blaustein, M. P. (1996) Mol. Pharmacol. 50, 1167-1177]. The three-dimensional structure of PiTX-K alpha was determined using NMR spectroscopy in order to understand its selectivity and affinity toward K+ channels. PiTX-K alpha was found to have an alpha-helix from residues 10 to 21 and two beta-strands (betaI, 26-28; betaII, 33-35) connected by a type II beta-turn to form a small antiparallel beta-sheet. Three disulfide bonds, which are conserved in all members of the charybdotoxin family (alpha-K toxins), anchor one face of the alpha-helix to the beta-sheet. The N-terminal portion of PiTX-K alpha has three fewer residues than other alpha-K toxins such as charybdotoxin. Rather than forming a third beta-strand as found for other alpha-K toxins, the N-terminal region of PiTX-K alpha adopts an extended conformation. This structural difference in PiTX-K alpha together with differences in sequence at Pro-10, Tyr-14, and Asn-25 (versus Ser-10, Trp-14, and Arg-25 in CTX) may explain why PiTX-K alpha does not block maxi-K+ channels. Differences in three-dimensional structure between PiTX-K alpha and charybdotoxin are also observed in both the tight turn and the loop that connects the first beta-strand to the alpha-helix. As a result, side chains of two residues (Tyr-23 and Arg-31) are in regions of PiTX-K alpha that probably interact with rapidly inactivating A-type K+ channels. The analogous residues in charybdotoxin are positioned differently on the toxin surface. Thus, the locations of Tyr-23 and Arg-31 side chains in PiTX-K alpha could explain why this toxin blocks A-type channels at much lower concentrations than does charybdotoxin.
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PMID:Solution structure for Pandinus toxin K-alpha (PiTX-K alpha), a selective blocker of A-type potassium channels. 906 3


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