Press
Release 28 March 2003 [PDF]
EMBL researchers discover a mechanism by which cells monitor estrogen.
The
hormone estrogen is recognized by most people because of its
important role in women's reproductive cycles. It also has
other functions in the body: it drives some types of cells
to replicate themselves, and it has been linked to the development
of tumors. Scientists at the European Molecular Biology Laboratory
[EMBL] in Heidelberg have now described a new model of how
cells constantly monitor their exposure to estrogen. This
work, which appears in the current issue of Molecular Cell,
provides new insights into the way estrogen influences the
activity of genes. It also suggests new ways to prevent cancer
cells from dividing.
Hormones serve as one of the body's express messenger services;
they are frequently used as a signal that tells cells to change
their functions or patterns of growth. Estrogen is a small
molecule that passes directly into cells; once inside, it
latches onto proteins called estrogen receptors that dock
onto DNA. As a result, genes are activated and new proteins
are produced, changing the cell's behavior.
The body reacts to both increases and decreases in amounts
of estrogen; switching a gene off can be just as important
as activating one. Recent experiments have given George Reid,
Michael Hübner and Raphaël Métivier in Frank
Gannon's laboratory a new view of how genes can respond to
changes in either direction.
Gannon's team has focused on estrogen receptors since they
are the main intermediaries between the estrogen hormone and
genes. Their latest work reveals that receptors don't stay
docked onto DNA very long; they regularly get stripped off
again and dismantled. New receptors arrive to take their place.
This cycle is essential to the way estrogen functions.
"It takes a two-step process for estrogen to switch on a gene,"
Reid says. "The hormone binds to the receptor and activates
it. This complex then docks onto DNA and turns on the gene.
If there is no estrogen around, 'unloaded' receptors still
attach themselves to DNA, but the gene won't be activated.
Now suppose that a lot of estrogen arrives, and that gene
needs to be activated. The inactive receptor needs to be moved
out of the way so that an active one can take its place."
Cells need to be equally sensitive to decreases in the amount
of estrogen. This means that genes which have been switched
on need to be turned off again. The mechanism is similar:
a receptor [in this case, the active form] has to be stripped
off the DNA.
"The first thing we discovered was a connection between gene
activity, estrogen receptors and the action of intracellular
molecular machines called proteasomes, which dismantle proteins,"
Reid says. "Jan Ellenberg's group helped us to watch how their
behavior changed under different conditions. If proteosomes
are active, a receptor can move around quickly, and this puts
it into position to contact the genes that respond to it.
Without proteasomes, estrogen receptors are immobilized. The
cycle is broken: fresh receptors don't get onto DNA."
Under normal circumstances, however, proteasomes are around
to help. The receptors dock onto DNA, and then they need to
be stripped off. The Gannon group showed that inactive receptors,
after binding to DNA, become loaded with another molecule
called ubiquitin, which marks them for destruction by proteasomes.
"With active receptors, the end result is the same, but the
sequence of events is a bit different," Reid says. "The active
receptor summons other molecules to read the information in
the DNA and transcribe it into RNA. After accomplishing this,
they, too, become loaded with ubiquitin. Again, this leads
to their removal from the gene. What we now understand is
that there's a continuous, active process that strips both
types of receptors – free and estrogen-bound – off the
DNA, and this is an intrinsic part of how the cell continuously
senses estrogen levels."
The constant removal of receptors from genes functions like
a sort of security camera that takes a fresh picture of estrogen
levels in the cell at regular intervals. It guarantees that
the cell can respond to changes when they occur.
"It also shows that this sensing system is dependent on the
behavior of other molecular components – ubiquitins, proteasomes
and all the cellular systems that control them," Reid says.
"That opens up new avenues for therapies in diseases that
involve estrogen. We know that the estrogen system is delicate;
it's also important, because it influences how some cells
differentiate and divide. These processes go wrong in certain
cancers, typically in the breast and the lining of the uterus.
Our findings suggest that you might be able to stop the proliferative
effects of estrogen by interfering with these other processes."
Source Article
Cyclic,
Proteasome–Mediated Turnover of Unliganded and Liganded
ER on Responsive Promoters Is an Integral Feature of Estrogen
Signaling
George Reid, Michael R. Hübner, Raphaël
Métivier, Heike Brand, Stefanie Denger, Dominique Manu,
Joël Beaudouin, Jan Ellenberg, and Frank Gannon
Mol. Cell 11 [3] 695–707 2003
Scientific Contacts
Frank Gannon
EMBL, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
Tel: +49 [0] 6221 387161
Fax: +49 [0] 6221 387518
E-mail: gannon@embl.deGeorge Reid
EMBL, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
Tel: +49 [0] 6221 387161
Fax: +49 [0] 6221 387518
E-mail: reid@embl.de |
