Methods of dissociating nongenotropic from genotropic activity of steroid receptors

A steroid, non-genetic technology used in biochemical equipment and methods, receptors/cell surface antigens/cell surface determinants, analytical materials, etc.

Inactive Publication Date: 2006-10-18
阿肯色大学评议会
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0043] As can be seen from the above illustration, despite significant progress towards understanding steroid signal transduction, there is a lack of understanding of how steroids mediate nongenic and genetic targeting

Method used

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  • Methods of dissociating nongenotropic from genotropic activity of steroid receptors
  • Methods of dissociating nongenotropic from genotropic activity of steroid receptors
  • Methods of dissociating nongenotropic from genotropic activity of steroid receptors

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0208] Regulation of osteoblast and osteocyte programming by estrogens and androgens in vivo and in vitro

[0209] Death

[0210] Compared with sham-operated controls, spinal osteoblast calvarial cell apoptosis was increased 10-fold and 8.3-fold, while bone cell apoptosis was increased 4-fold and 3.5-fold in ovariectomized or orchiectomized mice (Fig. 1A). After taking 17β-estradiol (E 2 ) in ovariectomized mice (unpublished data). To illustrate the mechanism of this effect, primary calvarial cell cultures and bone cell lines were used as in vitro models. E. 2 Or 5α-dihydrotestosterone (DHT) can inhibit the apoptosis induced by epipodophyllotoxin glucopyranoside in calvaria cells in a dose-dependent manner, and the maximum effect appears at 10 -9 -10 -8 M concentrations (Fig. 1B); the same results were obtained with MLO-Y4 cells (unpublished). When induced with any of the following three different pro-apoptotic stimuli, E 2 or DHT inhibited apop...

example 2

[0213] ER (α or β) or AR can transmit anti-apoptotic signals with equal efficiency, while

[0214] Regardless of whether the ligand is an estrogen or an androgen.

[0215] The estrogen receptor antagonist ICI182780 or the androgen receptor antagonist flutamide can inhibit E 2 The anti-apoptotic effects of DHT and DHT strongly suggest that the effects of the sex steroids are mediated through ER and AR.

[0216] Surprisingly, however, E 2 The anti-apoptotic effect of DHT can also be eliminated by flutamide, and the effect of DHT can be eliminated by ICI182780 ( figure 2 A). Consistent with this unexpected result, antihormones including ICI182780 have previously been shown by others to interact with various types of steroid receptors (Nawaz, Z., 1999, Cancer Res. 59, 372-376).

[0217] In order to determine E 2 The dependence of the anti-apoptotic effects of DHT and DHT on ER and AR, and to dissect the role of each receptor in the unexpected results obtained w...

example 3

[0220]The anti-apoptotic activity of ERα is located in the E (ligand binding) domain and requires

[0221] Extranuclear localization of the protein

[0222] Using ERα as a prototype, it was determined whether the domain required for anti-apoptotic activity of the sex steroid receptor is the same as that required for transcriptional activity ( Figure 3A ). The effects of several mutants of ERα on inhibiting apoptosis were compared. Some of these mutants have been disclosed previously and have been shown to produce the expected protein when transiently transfected into human cells such as the HeLa cells used in the present study (Schodin, D.J. et al., 1995, J.Biol.Chem.270, 31163-31171; Kraus, W.L.et al., 1997, J SteroidBiochem.Mol.Biol.63, 175-188; Ekena, K.et al., 1996, J.Biol.Chem. 271, 20053-20059; Ekena, K. et al., 1997, J. Biol. Chem. 272, 5069-5075; Montano et al., 1995, Mol. Endocrinol. 9, 814-825). In unpublished experiments, it has been found that m...

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Abstract

The present invention relates to fundamental discoveries for understanding the mechanism of non-gene targeting effects of steroids and its relation to gene targeting effects. It has been found that (i) non-gene targeting and gene targeting effects of steroids can be mediated through the same steroid receptors; (ii) both effects are ligand-induced; (iii) non-gene targeting effects occur is due to the ligand-inducing activity of the ligand-binding domain, which may be rapid and loose binding; (iv) gene targeting occurs due to the ligand of the DNA-binding domain of the steroid receptor induced activity, which is usually the result of a slower, stronger interaction; and (v) non-gene targeting of ligand interactions can be derived from gene targeting of ligand interactions separation so that selective reactions can be carried out. The present invention also discloses for the first time that certain steroids can induce non-gene targeting effects by binding to unrelated steroid receptors.

Description

[0001] federal funding [0002] This invention was funded in part through a grant from the National Institutes of Health. Accordingly, the United States federal government has certain rights in this invention. [0003] This application claims priority from the following patent applications: U.S. Patent Application Serial No. 60 / 211,287, entitled "Sex-Non-Specific Methods and Compositions for Improving Bone Mass," filed June 13, 2000; U.S. Patent Application Serial No. 60 / 274373, titled "A Method for Separating Non-Gene Direction from Transcriptional Activity of Steroid Receptors", filed on March 8, 2000. field of invention [0004] The present invention relates to the field of steroid signal transduction, and specifically discloses a method for separating the non-gene-directed effect of steroids from the gene-directed effect of steroids, and is used for screening the non-gene-directed effect that can induce the non-gene-directed effect without obviously inducing Steroid gene...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/705A01K67/027C07K14/47C12N9/12C12Q1/68G01N33/566
Inventor S·C·马诺拉加斯S·库斯特尼
Owner 阿肯色大学评议会
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