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.
Article: Modulation of oestrogen receptor
signalling by association with the activated dioxin
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,
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,
(addresses have been truncated.)
Why do you think your paper is highly
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.
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
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
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
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
Do you foresee any social or political implications for your
Our findings indicate that endocrine disrupting chemicals may interfere
with the sex hormone actions in wild animals. This is one of the caveats of
Shigeaki Kato, Ph.D., Professor
Institute of Molecular and Cellular Biosciences
The University of Tokyo