Featured Research

from universities, journals, and other organizations

Potential therapeutic target for Cushing's disease

Date:
May 7, 2013
Source:
Salk Institute for Biological Studies
Summary:
Scientists at the Salk Institute for Biological Studies have identified a protein that drives the formation of pituitary tumors in Cushing's disease, a development that may give clinicians a therapeutic target to treat this potentially life-threatening disorder.

Scientists at the Salk Institute for Biological Studies have identified a protein that drives the formation of pituitary tumors in Cushing's disease, a development that may give clinicians a therapeutic target to treat this potentially life-threatening disorder.

Related Articles


The protein, called TR4 (testicular orphan nuclear receptor 4), is one of the human body's 48 nuclear receptors, a class of proteins found in cells that are responsible for sensing hormones and, in response, regulating the expression of specific genes. Using a genome scan, the Salk team discovered that TR4 regulates a gene that produces adrenocorticotropic hormone (ACTH), which is overproduced by pituitary tumors in Cushing's disease (CD). The findings were published in the May 6 early online edition of Proceedings of the National Academy of Sciences.

"We were surprised by the scan, as TR4 and ACTH were not known to be functionally linked," says senior author Ronald M. Evans, a professor in Salk's Gene Expression Laboratory and a lead researcher in the Institute's Helmsley Center for Genomic Medicine. "TR4 is driving the growth and overexpression of ACTH. Targeting this pathway could therapeutically benefit treatment of CD."

In their study, Evans and his colleagues discovered that forced overexpression of TR4 in both human and mouse cells increased production of ACTH, cellular proliferation and tumor invasion rates. All of these events were reversed when TR4 expression was reduced.

First described more than 80 years ago, Cushing's disease is a rare disorder that is caused by pituitary tumors or excess growth of the pituitary gland located at the base of the brain. People with CD have too much ACTH, which stimulates the production and release of cortisol, a hormone that is normally produced during stressful situations.

While these pituitary tumors are almost always benign, they result in excess ACTH and cortisol secretion, which can result in various disabling symptoms, including diabetes, hypertension, osteoporosis, obesity and psychological disturbances. Surgical removal of the tumors is the first-line therapy, with remission rates of approximately 80 percent; however, the disease recurs in up to 25 percent of cases.

Drugs such as cabergoline, which is used to treat certain pituitary tumors, alone or in combination with ketoconazole, a drug normally used to treat fungal infections, have been shown to be effective in some patients with Cushing's disease. More recently, mefipristone-best known as the abortion pill RU-486-was approved by the FDA to treat CD. Despite these advances in medical therapy, the Salk scientists say additional therapeutic approaches are needed for CD.

"Pituitary tumors are extremely difficult to control," says Michael Downes, a senior staff scientist in the Gene Expression Laboratory and a co-author of the study. "To control them, you have to kill cells in the pituitary gland that are proliferating, which could prevent the production of a vital hormone."

Previous studies have found that, by itself, TR4 is a natural target for other signaling molecules in the pituitary. Small-molecule inhibitors that have been developed for other cancers could be potentially applied to disrupt this signaling cascade. "Our discovery," says Evans, a Howard Hughes Medical Institute investigator and holder of the March of Dimes Chair in Molecular and Developmental Biology, "might lead clinicians to an existing drug that could be used to treat Cushing's disease."

Other researchers on the study were Li Du, Marvin Bergsneider, Leili Mirsadraei, Stephen H. Young, William H. Yong and Anthony P. Heaney of the David A. Geffen School of Medicine at the University of California, Los Angeles, and Johan W. Jonker of the University of Groningen.

The study was supported by the National Institutes of Health, the Leona M. and Harry B. Helmsley Charitable Trust, the Samuel Waxman Cancer Research Foundation, the Jonsson Comprehensive Cancer Center at UCLA, and Ipsen/Biomeasure.


Story Source:

The above story is based on materials provided by Salk Institute for Biological Studies. Note: Materials may be edited for content and length.


Journal Reference:

  1. Li Du, Marvin Bergsneider, Leili Mirsadraei, Steven H. Young, Johan W. Jonker, Michael Downes, William H. Yong, Ronald M. Evans, and Anthony P. Heaney. Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease. PNAS, May 7, 2013 DOI: 10.1073/pnas.1306182110

Cite This Page:

Salk Institute for Biological Studies. "Potential therapeutic target for Cushing's disease." ScienceDaily. ScienceDaily, 7 May 2013. <www.sciencedaily.com/releases/2013/05/130507164239.htm>.
Salk Institute for Biological Studies. (2013, May 7). Potential therapeutic target for Cushing's disease. ScienceDaily. Retrieved November 22, 2014 from www.sciencedaily.com/releases/2013/05/130507164239.htm
Salk Institute for Biological Studies. "Potential therapeutic target for Cushing's disease." ScienceDaily. www.sciencedaily.com/releases/2013/05/130507164239.htm (accessed November 22, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Saturday, November 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

WFP: Ebola Risks Heightened Among Women Throughout Africa

WFP: Ebola Risks Heightened Among Women Throughout Africa

AFP (Nov. 21, 2014) Having children has always been a frightening prospect in Sierra Leone, the world's most dangerous place to give birth, but Ebola has presented an alarming new threat for expectant mothers. Duration: 00:37 Video provided by AFP
Powered by NewsLook.com
Could Your Genes Be The Reason You're Single?

Could Your Genes Be The Reason You're Single?

Newsy (Nov. 21, 2014) Researchers in Beijing discovered a gene called 5-HTA1, and carriers are reportedly 20 percent more likely to be single. Video provided by Newsy
Powered by NewsLook.com
Milestone Birthdays Can Bring Existential Crisis, Study Says

Milestone Birthdays Can Bring Existential Crisis, Study Says

Newsy (Nov. 21, 2014) Researchers find that as people approach new decades in their lives they make bigger life decisions. Video provided by Newsy
Powered by NewsLook.com
Ebola: Life Without School in Guinea

Ebola: Life Without School in Guinea

AFP (Nov. 21, 2014) Following the closure of schools and universities in Guinea because of the Ebola virus, students look for temporary work or gather in makeshift classrooms to catch up on their syllabus. Duration: 02:14 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins