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Developmental biology - Steroid Hormones

Rewriting How Steroid Hormones Work

A transporter system ferries steroids into cells and could have widespread benefits to human health...

A discovery by scientists at the University of California Riverside (UCR) may open up new ways to control steroid hormone-mediated processes affecting growth and development in insects and sexual maturation, immunity, and cancer progression in humans.

Published in Developmental Cell, researchers used the well-studied fruit fly model to show how a transporter protein allows a hormone to pass through the cell wall and into cells. The work was led by Naoki Yamanaka, an assistant professor of entomology at UCR and a member of the university's Institute for Integrative Genome Biology.
Steroid hormones are chemical messengers derived from cholesterol in the body. They regulate immune response, sexual maturation, cancer progression, metabolism, and inflammation. Despite their importance, little is known about how they cross cell membranes. Researchers in the field have long believed that simple diffusion through the cell walls explains the process.

Challenging this dogma, the UCR researchers believe that membrane transporters facilitate the transport of steroid hormones across cell membranes. The insect hormone studied, ecdysone, activates genes required for insect metamorphosis and molting as that insect moves from one stage of its life cycle into the next. As animal development is precisely timed, Yamanaka hypothesized that intake of specialized hormones might be needed to regulate these processes.

"Although the simple diffusion model has been prominent for all steroid hormones to date, it seemed logical, from a physiologic perspective, that cells would regulate ecdysone to achieve better control of its concentration," explains Yamanaka.
Using two separate genetic screens, researchers identified a potential gatekeeper - a transporter they named Ecdysone Importer (EcI). They then used the to create fruit flies without this transporter - after which all insect development completely stopped.

Supported by a $2.3 million grant from the National Institutes of Health (NIH), Naoki Yamanaka will now study the same transport pathway in mosquitoes, hoping to develop chemicals that inhibit steroid hormone entry into cells as a new way of pest control. If successful, the UCR research would be the first to show the function and significance of a steroid hormone importer in vivo in any organism. It would facilitate development of drugs that are more specific and less likely to result in resistance.

Transporters similar to EcI exist in all animals, including humans. Largely responsible for uptake of drugs, they can be detected at many blood-tissue interfaces and have the potential to be functionally highly specific.

Malaria Mosquito

Worldwide, mosquito-borne diseases cause millions of deaths each year. Above, mosquitoes carrying malaria alone cause more than 400,000 deaths, according to The World Health Organization.

In a collaboration led by Sachiko Haga-Yamanaka, Assistant Professor of Molecular, Cell, and Systems Biology, a UCR team is also searching for similar transporters in humans - work that is funded by a $1 million grant from the W. M. Keck Foundation.

Haga-Yamanaka: "If these transporters are found in humans, it will represent a paradigm shift in endocrinology. It would also open up the exciting possibility of developing chemical reagents that manipulate steroid hormone entry into cells, not just in insects but in humans. This could lead to new ways to manipulate a variety of steroid-related processes ranging from immune responses to cancer progression."

Insect steroid hormone ecdysone requires a membrane transporter to enter cells
Ecdysone Importer (EcI) is a member of the evolutionarily conserved SLCO superfamily
EcI functions cell autonomously to incorporate ecdysone from circulation

Steroid hormones are a group of lipophilic hormones that are believed to enter cells by simple diffusion to regulate diverse physiological processes through intracellular nuclear receptors. Here, we challenge this model in Drosophila by demonstrating that Ecdysone Importer (EcI), a membrane transporter identified from two independent genetic screens, is involved in cellular uptake of the steroid hormone ecdysone. EcI encodes an organic anion transporting polypeptide of the evolutionarily conserved solute carrier organic anion superfamily. In vivo, EcI loss of function causes phenotypes indistinguishable from ecdysone- or ecdysone receptor (EcR)-deficient animals, and EcI knockdown inhibits cellular uptake of ecdysone. Furthermore, EcI regulates ecdysone signaling in a cell-autonomous manner and is both necessary and sufficient for inducing ecdysone-dependent gene expression in culture cells expressing EcR. Altogether, our results challenge the simple diffusion model for cellular uptake of ecdysone and may have wide implications for basic and medical aspects of steroid hormone studies.

Yamanaka and Haga-Yamanaka, authors include Naoki Okamoto and Riyan Bittar from UCR and Raghuvir Viswanatha, Zhongchi Li, and Norbert Perrimon from Harvard Medical School.

The work is funded by the National Institutes of Health (R00 HD073239), the W.M. Keck Foundation and a Pew Biomedical Scholars Award.

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Oct 9, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

UC Riverside researchers reveal that membrane transporters (green) guide steroid hormones (orange circles) into cells, challenging a long-standing paradigm in endocrinology that simple diffusion is responsible for transporting disease. Credit: Haga-Yamanaka Lab, UC Riverside

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