Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Research focusing on why estrogenic hormones produce differing results

14.02.2005


New research is shedding light on why estrogenic hormones produce unintended results in women, giving hope to the idea that new drugs might reach their targets and work more effectively. Ultimately it could mean that postmenopausal women would know that hormone-replacement therapy would have only its intended result.



"It’s very difficult right now for women to make a choice about taking estrogen or other estrogen-like compounds, and, I think, it’s equally difficult for physicians to try to tell women what they should do," said Ann M. Nardulli, a professor in the department of molecular and integrative physiology at the University of Illinois at Urbana-Champaign.

Nardulli was the principal investigator of a study published in the Jan. 7 issue of the Journal of Biological Chemistry. In the study, Nardulli, doctoral student Jennifer R. Schultz and postgraduate researcher Larry N. Petz added fuel to the argument that the long-held model for how an estrogen receptor binds to DNA and, in turn, regulates gene transcription is need of retooling.


Nardulli’s team has found four discrete regions of the human progesterone receptor gene that confer hormone responsiveness. In the study, the activities of estradiol, tamoxifen, raloxifene and the soy phytoestrogens genestein and daidzein were examined and compared in uterine, mammary and bone cell lines. The researchers found vast differences based on the four regions. "The model has always been that the estrogen receptor binds to DNA to activate transcription, but now we show that that’s not always the case," Nardulli said. "Binding doesn’t occur equally well in different kinds of tissue, and it requires a broader vision on how transcription changes the functions in cells."

The value of hormone-replacement therapy has come under scrutiny because of links to various cancers. It’s also been discovered that women taking tamoxifen to protect against a relapse of breast cancer were more susceptible to getting uterine cancer. Other research, conducted at Illinois by food scientist William Helferich, has shown that the soy phytoestrogen genestein in doses similar to that found in supplements may negate the ability of tamoxifen to stop cancer redevelopment. Many women take soy supplements to control hot flashes.

The discovery in 1996 of a second estrogen receptor, or binding protein, began to rewrite conventional wisdom. Instead of just one receptor, now known as ER-alpha, researchers began studying the second one, ER-beta. ER-alpha is predominant in the uterus, liver, mammary gland, bone and cardiovascular systems; ER-beta is most expressed in the prostate, ovary and urinary tract.

Researchers also have found that many estrogen-responsive genes don’t have estrogen response elements -- long considered the cornerstone of estrogen receptor binding and transcription. Instead, as in the human progesterone receptor gene, they have multiple binding sites for activator proteins such as the four regions identified in Nardulli’s lab.

The four regions in progesterone receptor gene are known as AP-1 and Sp1 sites. The Sp1 sites, Nardulli said, are "pretty potent activators that get transcription going" when exposed to most of the hormones tested. The AP-1 sites by themselves were weak -- responsive somewhat to estrogen but not to the other hormones. Mutating an AP-1 site in the context of a larger gene region dramatically reduces transcription. Her lab’s findings also supported previous evidence that ER-alpha is much more potent than ER-beta.

"Turning on the expression of genes in a cell is not like turning on a light switch, because you have many different estrogen responsive genes in one cell," Nardulli said. "So, do you want to turn on all the genes to the same extent, or do you want to differentially regulate them? What researchers really would like to do is develop a hormone drug -- a ligand -- that targets exactly the tissues you want to affect without affecting any others."

Such work is already beginning to take shape in other labs at Illinois.

A team led by John A. Katzenellenbogen, a professor of chemistry, and his wife, Benita S. Katzenellenbogen, a professor of molecular and integrative physiology and of cell and structural biology in the College of Medicine at Urbana-Champaign, recently have produced a series of synthesized, non-steroidal estrogenic compounds that seek out and bind with ER-beta very selectively.

In a paper appearing online in advance of regular publication in the Journal of Medicinal Chemistry, published by the American Chemical Society, the Katzenellenbogens report that their compounds work on ER-beta nearly identically to estradiol, but they have almost no effect on the other estrogen receptor, ER-alpha.

"These compounds might prove useful as selective pharmacological probes to study the biological actions of estrogens mediated through ER-beta, and they might lead to the development of useful pharmaceuticals," they wrote in the journal paper.

Jim Barlow | EurekAlert!
Further information:
http://www.uiuc.edu

More articles from Life Sciences:

nachricht Topologische Quantenchemie
21.07.2017 | Max-Planck-Institut für Chemische Physik fester Stoffe

nachricht Topological Quantum Chemistry
21.07.2017 | Max-Planck-Institut für Chemische Physik fester Stoffe

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

Im Focus: On the way to a biological alternative

A bacterial enzyme enables reactions that open up alternatives to key industrial chemical processes

The research team of Prof. Dr. Oliver Einsle at the University of Freiburg's Institute of Biochemistry has long been exploring the functioning of nitrogenase....

Im Focus: The 1 trillion tonne iceberg

Larsen C Ice Shelf rift finally breaks through

A one trillion tonne iceberg - one of the biggest ever recorded -- has calved away from the Larsen C Ice Shelf in Antarctica, after a rift in the ice,...

Im Focus: Laser-cooled ions contribute to better understanding of friction

Physics supports biology: Researchers from PTB have developed a model system to investigate friction phenomena with atomic precision

Friction: what you want from car brakes, otherwise rather a nuisance. In any case, it is useful to know as precisely as possible how friction phenomena arise –...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

The technology with a feel for feelings

12.07.2017 | Event News

 
Latest News

NASA looks to solar eclipse to help understand Earth's energy system

21.07.2017 | Earth Sciences

Stanford researchers develop a new type of soft, growing robot

21.07.2017 | Power and Electrical Engineering

Vortex photons from electrons in circular motion

21.07.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>