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 Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute

nachricht Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>