New Look At Protein Recycling And The Disease Process

Ubiquitination is a key part of the process by which proteins are broken down and recycled within human cells. But understanding how ubiquitination works and its role in disease has eluded researchers for decades.

Now a key part in this puzzle has been solved by researchers at Weill Cornell Medical College who developed a method to clarify the role that ubiquitination plays in a variety of diseases, including breast cancer and Parkinson’s disease. It is hoped that their discovery will lead both to better treatments as well as finding ways to delay and even prevent these illnesses.

The research team’s breakthrough findings were published online in the July 18 issue of Nature Biotechnology. Since then, they have had inquiries from researchers around the world.

Cell division, DNA repair, and parts of the immune defense system are all governed by ubiquitin-mediated protein degradation. However, when this process does not work correctly, it causes illnesses, including cancers.

“We know that the cell functions as a highly efficient checking station where proteins are built up and broken down,” says Dr. Samie R. Jaffrey, associate professor of pharmacology at Weill Cornell Medical College and the lead author of the paper.

“During this process, broken proteins are given a molecular label and then fed into proteasomes where they are destroyed. The ‘label’ is the molecule ubiquitin, which fastens to the protein to be destroyed and accompanies it to the proteasome where it is ‘recognized,’ signaling that a protein is on the way for disassembly.”

In his studies of brain development, Dr. Jaffrey had observed that proteins were being rapidly ubiquitinated, and that this ubiquitination was required to enable neurons to form proper connections in the brain. However, methods to identify the proteins that were being degraded during this dynamic process were not available. “We predicted that finding the proteins that were ubiquitinated would tell us how neurons form connections throughout the brain.”

To test their hypothesis, the team developed a new strategy to profile ubiquitination across the proteome by utilizing a monoclonal antibody that allows ubiquitinated proteins to be recovered from tissue extracts and then quantified using high-throughput mass spectrometry. The ubiquitination targets included proteins that are involved in brain development, as well as disease-related proteins such as BRCA-1 (one of two breast cancer genes) and TNF receptor-associated proteins — genes involved in cell growth, cell division, and repair of damage to DNA.

In addition to identifying several hundred proteins that were ubiquitinated, they were also able to identify the specific portion of the protein that was modified. Nearly three quarters of the proteins were not previously known to be ubiquitinated and 92 percent of these ubiquitination sites were not previously known. Strikingly, the ubiquitin tags were observed to rapidly increase following treatments that stimulated cell growth or death, suggesting that ubiquitination may regulate these cellular processes.

“Ubiquitination has long been extremely difficult to study, but our method has opened the door to clarifying the role of ubiquitination in a variety of diseases,” Dr. Jaffrey says. “A surprisingly number of diseases have been linked to defective ubiquitination, such as breast cancer, myeloma and Parkinson’s disease. We hope our findings will also allow researchers to screen drugs for their ability to inhibit ubiquitination and ultimately come up with better treatments.”

In 2009, Dr. Jaffrey was among a select group of researchers awarded a competitive grant from the National Institutes of Health (NIH) called the NIH Director’s Transformative R01 (T-R01) Awards. According to the NIH, the grants were given to “encourage investigators to explore bold ideas that have the potential to catapult fields forward and speed the translation of research into improved health.”

Besides Dr. Jaffrey, contributing authors to the study published in Nature Biotechnology included Weill Cornell’s Dr. Guoqiang Xu, and Jeremy S. Paige, a graduate student of the Department of Pharmacology.

Dr. Jaffrey, is a co-founder and co-owner of Lucerna Technologies, and is a member of its advisory board. Lucerna Technologies is a biotechnology company focused on developing and commercializing nucleic acid-based florescent sensors for point-of-care therapeutic diagnostics. Additionally Lucerna offers antibodies for proteomic research.

Source: Weill Cornell Medical College

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