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At least 865 records · Page 48Linked to original sources
PubMed1997

Cloning and characterization of a 77-kDa oestrogen receptor isolated from a human breast cancer cell line.

We have cloned and characterized a 77-kDa oestrogen receptor (ER) from an oestrogen-independent subclone of the MCF-7 human breast cancer cell line. This receptor contains an in-frame, tandem duplication of exons 6 and 7, located in the steroid-binding domain of the ER. This mutation has abrogated ligand binding, but not DNA binding, in this mutant ER. We previously described the partial structure of a unique oestrogen receptor (ER) that is expressed in an oestrogen-independent MCF-7:2A subclone of the breast cancer cell line MCF-7 (Pink JJ, Wu SQ, Wolf DM, Bilimoria MM, Jordan VC 1996a, Nucleic Acids Res 24 962-969). Sequence analyses determined the molecular weight of this 80-kDa ER to be 77 kDa, and hereafter this protein will be designated as ER77. Examination of the entire coding sequence of the ER77 mRNA indicates that it contains a tandem duplication of exons 6 and 7. Using a coupled transcription/translation system, a 77-kDa ER, which corresponds to the protein observed in the MCF-7:2A cells, was expressed. The ER77 protein does not bind the ligands [3H] oestradiol or [3H]tamoxifen aziridine. In DNA binding gel shift assays, the in vitro synthesized ER77 binds to a consensus vitellogenin A2 oestrogen-response element. In transient transfection experiments, the mutant ER, alone or in combination with the wild-type ER, does not induce expression of an oestrogen-responsive luciferase reporter construct. In fact, expression of the ER77 in the ER-positive T47D:A18 cell line inhibits E2-induced luciferase expression. Overexpression of wild-type ER in T47D:A18 cells leads to elevated constitutive expression of the luciferase reporter, which was inhibited by co-transfection with ER77. These data suggest that the ER77 can interfere with normal ER activity and does not act as a constitutive activator of oestrogen-independent growth in MCF-7:2A cells. Consequently, the constitutive growth observed in MCF-7:2A cells is probably the result of other ER-mediated pathways.

Amino Acid Sequence↗
PubMed2003

First synthesis of 2',3'-epimino-carbocyclic nucleosides.

The preparation of 2',3'-epimino-carbocyclic analogues of adenosine is reported. The reaction of p-tosyl azide with N-substituted 2-azabicyclo[2.2.1]hept-5-en-3-one (ABH) (1a) provided aziridine-fused ABH (2), which was converted to 2',3'-epimino-carbocyclic nucleosides (11).

Adenosine↗
PubMed2003

Stereoselective aza-Diels-Alder reactions with 2H-azirines as dienophiles furnishing highly functionalized tetrahydropyridines.

Highly diastereoselective Lewis acid mediated aza-Diels-Alder reactions of chiral auxiliary derivatized 2H-azirines have been accomplished for the first time, yielding bi and tri-cyclic heterocyclic compounds, comprising aziridine and tetrahydropyridine substructures, in up to 97% de; with the absolute stereochemistry of the major product confirmed by X-ray crystallography.

Journal Article↗
PubMed2005

A short, versatile chemical synthesis of L- and D-amino acids stereoselectively labelled solely in the beta position.

L- and D-Amino acids which are stereoselectively labelled solely either in the 3-pro-R or in the 3-pro-S-positions have been prepared by a relatively short chemical synthesis in ee of 81 to 86%. This involves Sharpless' aminohydroxylation and cyclisation with inversion of stereochemistry at C-2 to give the stereoselectively labelled D- and L-aziridines and 10a and 10b, and 8a and 8b. These have previously been modified and cleaved with inversion of stereochemistry at C-3 using a number of nucleophiles to give a large variety of protected amino acids. Synthesis of the labelled D- and L-beta-chloroalanines 22a and 22b and 25a and 25b is described here.

Journal Article↗
PubMed2005

Mitsunobu dehydration of N-Boc neomycin B.

Reaction of hexa-N-Boc neomycin B with TPP and DIAD in toluene results in the formation of an epoxide in ring IV, not an aziridine or azetidine as previously reported.

Epoxy Compounds↗
PubMed2001

Nitric oxide and free stable nitroxyl radicals in the mechanism of biological action of the spin-labeled compounds.

A comparison of more important physical, chemical and biological properties of the nitric oxide (NO) and free stable nitroxyl radicals (nitroxides) on the base of their structural similarity is made in the article. The active moiety in the nitroxide molecule represents a sterically hindered nitric oxide. The mechanisms of biological action of the nitroxides and especially of their derivatives with antitumor agents from the groups of nitrogen mustards, nitrosoureas, aziridines and triazenes (spin-labeled compounds) is explained through the biological activities of sterically hindered NO. Similarly to NO, nitroxides also can react with superoxide anion radical (O(2)(-)), they possess superoxide dismutase (SOD) mimetic action. While the interaction of NO with O(2)(-)yields very toxic peroxynitrite (ONOO(-)), its formation is strongly limited in the presence of a nitroxide. It is known that the nitrosourea antitumor drugs, like lomustine (CCNU) and carmustine (BCNU), showed high general toxicity, one of the reasons for that probability is the formation of NO, and subsequently of ONOO(-), during their metabolism. The biological investigations of the nitroxides showed their considerably lower general toxicity that could be explained with the SOD-mimetic action of the nitroxide present in their molecule.

Antineoplastic Agents↗
PubMed2005

A persistent pesticide residue and the unusual catalytic proficiency of a dehalogenating enzyme.

The soil of potato fields in The Netherlands harbors bacteria with the ability to metabolize 3-chloroacrylic acid, generated by the degradation of a pesticide (1,3-dichloropropene) that entered the environment in 1946. From examination of rate constants at elevated temperatures, we infer that the half-time at 25 degrees C for spontaneous hydrolytic dechlorination of trans-3-chloroacrylic acid is 10,000 years, several orders of magnitude longer than half-times for spontaneous decomposition of other environmental pollutants such as 1,2-dichloroethane (72 years), paraoxon (13 months), atrazine (5 months), and aziridine (52 h). With thermodynamic parameters for activation similar to those for the spontaneous hydration of fumarate at pH 6.8, this slow reaction proceeds at a constant rate through the pH range between 2 and 12. However, at the active site of the enzyme 3-chloroacrylate dehalogenase (CaaD), isolated from a pseudomonad growing in these soils, hydrolytic dechlorination proceeds with a half-time of 0.18 s. Neither k(cat) nor k(cat)/K(m) is reduced by increasing solvent viscosity with trehalose, implying that the rate of enzymatic dechlorination is controlled by chemical events in catalysis rather than by diffusion-limited substrate binding or product release. CaaD achieves an approximately 10(12)-fold rate enhancement, matching or surpassing the rate enhancements produced by many enzymes that act on more conventional biological substrates. One of those enzymes is 4-oxalocrotonate tautomerase, with which CaaD seems to share a common evolutionary origin.

Acrylates↗
PubMed1988

Nuclear estrogen receptor molecular heterogeneity in the mouse uterus.

Holomeric estrogen receptor (ER) prepared from ovariectomized mouse uteri displays heterogeneous electrophoretic mobility when analyzed by NaDodSO4/PAGE. ER derived from nuclei (ERn) appears as a closely spaced doublet having apparent molecular masses of 66.4 and 65 kDa, while ER from the cytosolic compartment (ERc) has a single band of 65 kDa. Both partially purified ERc and the 8S form of unactivated ERc show only the 65-kDa band. The appearance of the ERn doublet is hormonally inducible, and the relative proportions of the two doublet bands are influenced by the type of hormone treatment, with weakly estrogenic compounds yielding the lower band as predominant while potent estrogens increase the proportion of the upper band. Steroid binding of the ERn doublet was determined by [3H]tamoxifen aziridine affinity labeling of both the 66.4- and the 65-kDa peptides; binding to the 65-kDa peptide was predominant. The ERn doublet displays a time dependency after estrogen administration with maximal amounts occurring in a bimodal fashion at 1 and 8 hr.

Animals↗
PubMed1988

Immunodetection of estrogen receptor in epithelial and stromal tissues of neonatal mouse uterus.

The tissue distribution and levels of estrogen receptor in neonatal mouse uterine tissue were determined in epithelial and stromal fractions separated by mild enzymatic treatment. Proteins of the isolated fractions were separated by gel electrophoresis and receptor was detected on immunoblots with monoclonal antibody H-222. Estrogen receptor protein was detectable in samples of reproductive tract tissue from 5- and 10-day-old mice. The level of receptor in 5-day-old animals was lower per unit DNA in epithelial cells than in stroma. Receptor levels were increased in both tissue types after treatment with diethylstilbestrol, but not with progesterone. Receptor protein present in these neonatal tissues was able to bind steroid as evidenced by affinity labeling with tamoxifen aziridine. Immunohistochemistry on sections of uteri from 4- and 10-day-old mice confirmed the biochemical results and indicated lower nuclear straining in epithelial cells than in stromal cells of uteri of 4-day-old mice. These results demonstrated that estrogen receptor protein is present in both epithelium and stroma of the neonatal mouse uterus, but at a higher level in stromal cells.

Animals↗
PubMed1995

Functional estrogen receptors in a human preosteoclastic cell line.

The primary biological effect of the estrogen estradiol-17 beta (17 beta E2) on bone is to decrease bone resorption. However, whether 17 beta E2 affects osteoclast differentiation or function directly or through its action on osteoblasts is unclear. To investigate this question we examined the human preosteoclastic cell line FLG 29.1 for evidence of functional estrogen receptors (ERs). Southern blotting of reverse transcription-PCR amplification products with a 32P-labeled cDNA probe for the human ER mRNA demonstrated that FLG 29.1 cells express ER mRNA. Binding of [3H]17 beta E2 to nuclear ERs was steroid specific with approximately 400 saturable, high affinity (Kd approximately 1 nM) binding sites per cell nucleus. Nuclear ERs covalently labeled with [3H]tamoxifen aziridine showed an apparent molecular weight of 65,000 by SDS/PAGE and Western blotting with the D75 monoclonal antibody to human ER. Pretreatment of cells with 0.1, 1.0, or 10 nM 17 beta E2 induced a dose- and time-dependent specific binding of progesterone to FGL 29.1 cells, and stimulation of the cells with 10 nM and 100 nM 17 beta E2 significantly (P < 0.05) reduced cell proliferation. Transcriptional activity of the ER gene was detected by transient transfection of cells with the pERE-BLCAT plasmid containing the estrogen response element for the vitellogenin A2 gene and the bacterial chloramphenicol acetyltransferase reporter gene. Treatment of FLG 29.1 cells with 10 nM 17 beta E2 increased chloroamphenicol acetyltransferase expression from 5- to 29-fold compared to controls. These observations suggest a potential role for estrogen in osteoclastogenesis.

Adenocarcinoma↗