Navigation Links
Scripps Research scientists identify new mechanism regulating daily biological rhythms
Date:11/11/2010

JUPITER, FL, November 9, 2010 For Immediate Release Scientists from the Florida campus of The Scripps Research Institute have identified for the first time a novel mechanism that regulates circadian rhythm, the master clock that controls the body's natural 24-hour physiological cycle. These new findings could provide a new target not only for jet lag, shift work, and sleep disturbances, but also for disorders that result from circadian rhythm disruption, including diabetes and obesity as well as some types of cancer.

The study is published in the November 12, 2010 edition (Volume 285, Number 45) of the Journal of Biological Chemistry.

"It's well known that the nuclear receptors RORα and REV-ERBα regulate expression of the gene BMAL1, which is vital to virtually every aspect of human physiology and a core component of the circadian clock," said Tom Burris, a professor in the Department of Molecular Therapeutics at Scripps Florida who led the study. "BMAL1 functions as an obligate heterodimer (only working as a dimer with a partner) with either CLOCK or NPAS2 so it was unclear how RORa and REV-ERBa could control this complex. In this study, we show that both partners are targets. As we understand more about the relationship between these receptors and their gene targets, we can consider the possibility of modulating the body's core clock, especially as we continue to develop synthetic ligands targeting these two nuclear receptors."

Circadian rhythms are conserved across a wide variety of organisms, from Drosophila (fruit flies) to humans. In mammals, these rhythms respond to light signals and are controlled by the "master clock" in the brain. In the periphery, semi-autonomous clocks can respond to signals from the brain and from other cues including nutrient status. Disorders linked to dysfunctional circadian rhythms can be severe and potentially deadly, Burris said.

"When you're dealing with circadian rhythm, the most obvious disease target is sleep for people who do shift work, critical jobs like police work, fire fighting, and medicine," he said. "If circadian rhythm is disrupted, you're prone to metabolic disorders like diabetes and obesity and even breast cancer because the core clock is closely linked to the cell cycle. If your clock goes awry, you run the risk of your cell cycle going awry as well."

The Role of Nuclear Receptors

Nuclear receptors are proteins that recognize and regulate hormones as well as other molecules. As a result, they control an organism's metabolism by activating gene expression.

The study found that oscillations in the expression of RORα and REV-ERBα not only influence the pattern of circadian expression of BMAL1, but also of NPAS2, a protein that is part of the circadian clock. The fact that NPAS2 is a target of both receptors suggests that there is a specific mechanism that coordinates the relative levels of each receptor to maintain correct circadian function..

"Based on the fact that BMAL1 and NPAS2 work together within the circadian clock, it seems highly unlikely that these two nuclear receptors would only regulate one of them," Burris said. "Our study shows for the first time that, like BMAL1, NPAS2 is also a direct target for RORα and REV-ERBα. This discovery makes this complex a very good therapeutic target."

The expression of RORα and REV-ERBα follows a 24-hour circadian pattern (with opposing phases) leading to the correct circadian pattern of gene expression of BMAL1 and NPAS2.

"We think it's something of a competition between these two receptors for binding to promoters of these genes that triggers either the activation (RORα) or repression (REV-ERBα) of the gene," Burris said.

Nuclear receptors make tempting drug targets because they can bind directly to DNA and activate genes through specific ligandsmolecules that affect receptor behaviorsuch as the sex hormones, vitamins A and D, and glucocorticoids, which modulate the body's response to stress. Nuclear receptors have been implicated in a number of cancers, including prostate, breast, and colon cancers, and other diseases as well, including type 2 diabetes, atherosclerosis, and metabolic syndrome.

The other important aspect of nuclear receptors is their practicality. Scientists can design small molecule therapeutics to force them to change their ways. Burris said that he has already identified several new synthetic ligands (drug like molecules) for both receptors.


'/>"/>

Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute
Source:Eurekalert

Related biology news :

1. Scripps Research team watches formation of cells protein factories for first time
2. Landenberger Foundation awards grant to Scripps Florida scientist to study HIV
3. Entire issue of scientific journal devoted to center headed by Scripps Research Scientists
4. Scripps Research study challenges conventional theory of modern drug design
5. Scripps Research scientists develop novel test that identifies river blindness
6. Scripps researchers, UCSD chemists to create center devoted to chemistrys influence on climate
7. Scripps Research scientists win $65 million in new grants to reveal form and function of proteins
8. Scripps scientists develop test providing new pathway for identifying obesity, diabetes drugs
9. Scripps research team wins $5.1 million to develop DNA sequencing technology
10. Team led by Scripps Research scientist identifies new gene for memory
11. Seafood stewardship questionable: UBC-Scripps experts
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/2/2016)... --  The Weather Company , an IBM Business (NYSE: ... in which consumers will be able to interact with IBM ... voice or text and receive relevant information about the product ... have long sought an advertising solution that can create a ... and valuable; and can scale across millions of interactions and ...
(Date:5/20/2016)... 2016  VoiceIt is excited to announce its ... By working together, VoiceIt and VoicePass will ... VoicePass take slightly different approaches to voice biometrics, ... and usability. ... partnership. "This marketing and technology partnership ...
(Date:5/3/2016)... VILNIUS, Lithuania , May 3, 2016 /PRNewswire/ ... today released the MegaMatcher Automated Biometric Identification ... deployment of large-scale multi-biometric projects. MegaMatcher ABIS can ... and accuracy using any combination of fingerprint, face ... of MegaMatcher SDK and MegaMatcher ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... ... June 23, 2016 , ... Charm Sciences, Inc. ... test has received AOAC Research Institute approval 061601. , “This is another AOAC-RI ... stated Bob Salter, Vice President of Regulatory and Industrial Affairs. “The Peel Plate ...
(Date:6/23/2016)... ON (PRWEB) , ... June 23, 2016 , ... STACS ... DNA Technical Leader at the Arkansas State Crime Laboratory, has joined STACS DNA as ... the STACS DNA team,” said Jocelyn Tremblay, President and COO of STACS DNA. “In ...
(Date:6/23/2016)... 2016 On Wednesday, June 22, 2016, ... 0.22%; the Dow Jones Industrial Average edged 0.27% lower to ... down 0.17%. Stock-Callers.com has initiated coverage on the following equities: ... (NASDAQ: NKTR ), Aralez Pharmaceuticals Inc. (NASDAQ: ... BIND ). Learn more about these stocks by accessing their ...
(Date:6/23/2016)... ReportsnReports.com adds 2016 global ... pharmaceuticals section with historic and forecast data along ... Complete report on the Cell Culture ... companies and supported with 261 tables and figures ... The Global Cell Culture Media Industry ...
Breaking Biology Technology: