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EMERGING RESEARCH FRONTS - 2008

Shigeaki Kato talks with ScienceWatch.com and answers a few questions about this month's Emerging Research Front in the field of Pharmacology & Toxicology. The author has also sent along images of their work.
Kato Article: Modulation of oestrogen receptor signalling by association with the activated dioxin receptor
Authors: Ohtake, F;Takeyama, K;Matsumoto, T;Kitagawa, H;Yamamoto, Y;Nohara, K;Tohyama, C;Krust, A;Mimura, J;Chambon, P;Yanagisawa, J;Fujii-Kuriyama, Y;Kato , S
Journal: NATURE, 423 (6939): 545-550 MAY 29 2003
Addresses: Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, 1-1-1 Yayoi, Tokyo 1130032, Japan.
Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, Tokyo 1130032, Japan.
Japan Sci & Technol, SORST, Kawaguchi, Saitama 3320012, Japan.
(addresses have been truncated.)

Why do you think your paper is highly cited?

The molecular basis of the reported cross-talk of estrogen and dioxin signalings as described in this paper was quite new conceptually, primarily because their receptors do not belong to the same class of transcription factors. Estrogen receptor (ER) is a nuclear receptor, while dioxin receptor (AhR) is a bHLH-type transcription factor. Both receptors respond to cognate fat-soluble ligands in order to activate target genes, and the cellular signalings in this respect are similar to each other but quite distinct in protein structure.

 
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The evidence had suggested for some time that dioxins may modulate estrogen signalings in cultured cells and intact animals; however, the molecular mechanism was not revealed at the molecular level. Our findings provided a missing piece in the estrogen receptor signaling process. Activated aryl hydrocarbon receptor (AhR) behaved as a transcription co-activator for estrogen-unbound ER without DNA binding. These findings brought forth a new idea that AhR activated by dioxins serve as a co-regulator for sex hormone receptors, in addition to the classical idea that AhR is a DNA binding transcription factor.

Regarding the nuclear ER, prior to this report, a description of the activation of ER function in the absence of ER agonists hadn't yet been outlined. From these findings, it was implied that ligand-unbound nuclear receptors could be activated through protein-protein interaction.

Does it describe a new discovery, methodology, or synthesis of knowledge?

Yes, it is. This report implies for the first time that ligand-unbound nuclear receptors can be activated through other transcription factors. This is a fundamental quality of ER functions and estrogen signaling.

Would you summarize the significance of your paper in layman's terms?

This report described a cross-talk between endocrine disruptors and nuclear receptor signaling and uncovered a mechanism of the adverse effects of environmental toxins whenever they act as dioxin receptor ligands.

AhR localizes in cytosol, and upon ligand binding, AhR is translocated into the nucleus. As a classical idea, activated AhR binds to specific DNA sequences (XREs) in the promoters of target genes like p450 family members. However in this report, we showed that activated AhR accommodates ER on the target sites (ERE) of the ER target gene promoters.

In the absence of estrogen, activated AhR induced the transcriptional function of ER. Those results were obtained in the cultured cells, but similar cross-talk on the ER target gene regulations and estrogen-induced cell proliferation was also seen in intact mice. However, in either AhR KO mice or ER KO mice, such cross-talk was invisible.

How did you become involved in this research and were any particular problems encountered along the way?

We had initially shown a MAP kinase-mediated crosstalk between mitogen and estrogen signaling in 1995. Then my group demonstrated a convergence between vitamin D and TGF-b signaling through co-activation of vitamin D receptor by TGF-b signal transducers, smads, in 1999. We then started to uncover the molecular basis as to why the dioxin receptor ligands modify ER-mediated signaling. The cell culture experiments were quick and reproducible, but the same animal experiments took a much greater effort in order to discover proper experimental conditions.

Where do you see your research leading in the future?

We are curious about the biological actions of estrogen from animal to chromatin levels. In continuation of this project, we have recently reported in the article entitled: "Dioxin receptor is a ligand-dependent E3 ubiquitin ligase," (Nature 446: 562–66, 2007), that AhR is a ligand-dependent component of E3 ligase complex to ubiqutinate and degrade sex hormone receptor proteins. AhR is thus an atypical bHLH-type transcription factor, and dioxins appear to control gene expressions as well as define the half-lives of proteins through AhR.

In a more general sense, the fat-soluble ligands for nuclear receptors and AhR may be signals for targeted protein degradation. To test this idea, a number of projects are currently underway in my laboratory. In addition, we are concentrating our efforts on identifying transcriptional co-regulators for ER, while characterizing them for epigenetic controls. Apart from such molecular dissection of estrogen signalings in nuclear receptors, we are doing quite a bit of research to define ER function in intact animals. Particularly, we are focusing on ER function in bone, and last year we reported in the journal Cell that activated ER in mature osteoclasts induces osteoclastic apoptosis, leading to the suppression of bone resorption.

Do you foresee any social or political implications for your research?

Our findings indicate that endocrine disrupting chemicals may interfere with the sex hormone actions in wild animals. This is one of the caveats of nature.

Shigeaki Kato, Ph.D., Professor
Institute of Molecular and Cellular Biosciences
The University of Tokyo
Bunkyo-ku, Tokyo



2008 : April 2008 : Shigeaki Kato