Getting a handle on sensitive cycles

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.”