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Hormone Cycling Found to Affect Gene Activity

Intermittent signaling by steroid hormones can affect the way genes are expressed in rodents, according to research by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, and the Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Bristol, England. The findings were published online Aug. 16, 2009, and will appear in the September 2009 issue of Nature Cell Biology. These results provide the basis for a new view of gene regulation by hormone receptors.

The release of hormones by the body’s glands can occur in an episodic, or ultradian, pattern, which consists of repeated periods of release that take place throughout a 24-hour, or circadian, period. Glucocorticoid hormones, which were investigated in this study, are steroid hormones secreted by the adrenal glands that are involved in a large variety of animal and human physiological responses. Glucocorticoids act through the glucocorticoid receptor, which is expressed in almost every cell in the body and regulates genes controlling development, metabolism, and immune response.

Studies of the glucocorticoid receptor typically assess gene responses after long-term stimulation with synthetic hormones. However, such treatments may not fully replicate the actual situation in living animals because, in addition to being released from the adrenal glands in a 24-hour circadian pattern, these hormones are also released in a pulsing mode, cycling approximately every hour, in what is referred to as ultradian cycling.

In this new study, the researchers demonstrate that ultradian hormone stimulation induces the pulsed expression of genes (known as gene pulsing) over the same period, both in cultured cells and in animal models. Initially, the researchers administered corticosterone, a naturally occurring glucocorticoid hormone in rodents, in a pulsed manner to cultured mouse cells and then observed that the levels of newly synthesized RNA from glucocorticoid receptor-regulated genes tracked precisely with the hormone pulses.

To determine whether gene pulsing occurs in live animals, the researchers removed adrenal glands from rats to eliminate their body’s source of glucocorticoids and then treated the animals with an ultradian corticosterone regimen. They observed a response similar to that found in the cultured cells. For example, a corticosterone-responsive gene was expressed in a pulsed pattern. They also observed that, when corticosterone was administered in a constant (non-cycling) manner, RNA levels were substantially higher than when treatments were given in an ultradian manner.

It is likely that the release of glucocorticoids in transient pulses from the adrenal glands has important biological consequences, because it has been conserved during the evolution of many species. This phenomenon has also been described for several other mammalian hormones and, in some cases, is known to be required for the proper physiological functioning of organisms.

The reported research results argue that gene pulsing regulated by glucocorticoid receptors is directly linked to varying levels of gene activity. According to the senior author, Gordon Hager, Ph.D., head of the Lab of Receptor Biology and Gene Expression in the Center for Cancer Research, NCI, "Ultradian secretion, described widely in mammalian species, induces a pattern of glucocorticoid receptor action that leads to transient pulses of gene transcription, rather than continuous expression. This insight opens novel approaches for the development of synthetic glucocorticoids."

The researchers conclude that, considering the wide therapeutic use of glucocorticoids for arthritis and even some cancer indications, further studies to replicate their results and follow-up studies in humans are clearly needed. Such studies will help to define the potential role of ultradian application of glucocorticoid receptor therapy.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
Reference: Stavreva, D.A., Wiench, M., John, S., Conway-Campbell, B.L., McKenna, M.A., Pooley, J.R., Johnson, T.A., Voss, T.C., Lightman, S.L., and Hager, G.L. Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nat. Cell Biol. Online August 16, 2009. In print September 2009. Vol. 11, No. 9. Manuscript #NCB-H15221B.

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