11:18am Thursday 23 November 2017

Unlikely Partners? Cell's Waste Disposal System Regulates Body Clock Proteins, Finds Penn Study

PHILADELPHIA – Rhythmic expression of key genes is essential for maintaining proper timekeeping of the body’s clock. In addition, rhythmic degradation of clockwork proteins is also crucial. However, surprisingly, researchers know little about these specific processes.

A new Penn-led study describes a new genome screen that identified partner molecules of cell-waste disposal proteins. The team led by John Hogenesch, PhD, a professor of Systems Pharmacology and Translational Therapeutics in the Perelman School of Medicine at University of Pennsylvania and Jason DeBruyne, PhD, a former postdoctoral fellow in the Hogenesch lab and now an assistant professor at Morehouse School of Medicine in Atlanta, applied their new method to identifying other clock partners that target a multipurpose cell nucleus receptor for disposal. Their findings were published online ahead of print in the Proceedings of the National Academy of Sciences

“Our goal was not really to study clock biology,” said senior author Hogenesch. “Rather, our aim was to develop a genome-wide screen to identify key players involved in protein stability and breakdown.”
 
The proteins they were looking for are called ligases. These recognize specific proteins and direct the addition of a molecule onto waste proteins to dispatch the protein to be recycled to the proteosome. This is the cell compartment that breaks up used proteins into its basic amino acids.
To validate the screen, the team tagged several of their favorite clock proteins with a short protein tag that’s easily recognized by antibodies. The team then used high throughput imaging to see what ligases increase and decrease the levels of their favorite clock proteins in cells. They found that the ligase Fbxl3 was a regulator of Cry proteins, critical components of the core clock. They also found that a protein called Seven in absentia 2 (Siah2) is a key regulator of the turnover of a well-studied, clock nuclear protein called RevErbα on a 24-hour cycle.

Certain ligases, like Fbxl3, can be targeted with small molecules. “These ligases are being actively developed in drug discovery efforts,” Hogenesch noted. “Most proteins don’t bind with small molecules. With this screen, we may be able to overcome that limitation by finding the ligase that regulates their levels and function. Small molecules against the ligase, then, could indirectly regulate the amount and therefore activity of the ‘undruggable’ protein.”

The researchers hope that by applying this new method, more ligase drug targets can be found and developed into new therapies across the spectrum of health challenges.
 
Coauthors are Julie E. Baggs and Trey K. Sato, both from Penn.
 
This work was supported by the National Institute of Mental Health P50 Conte Center (MH074924) the National Institute of Neurological Disorders and Stroke (R01 NS054794, U54 NS083932), the National Institute of Minority Health and Health Disparities (8G12MD007602); the National Institute General Medical Sciences (SC1 GM109861), and the Defense Advanced Research Projects Agency (DARPA-D12AP00025).

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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.9 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report‘s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $409 million awarded in the 2014 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center — which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report — Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2014, Penn Medicine provided $771 million to benefit our community.


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