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Discovery boom in Southern California
October 2015
by Jeffrey Bouley  |  Email the author
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SAN DIEGO—Summer was a busy time at the University of California, San Diego (UCSD), and not simply because students were trying to cram in more beach time before the academic year roared into full force again. Here is a roundup of three therapeutics discovery breakthroughs announced by UCSD over the course of about a month recently.
 
Corrected protein structure reveals drug targets for cancer, neurodegenerative diseases
 
A UCSD study in August revises the previously published structure of the protein kinase C (PKC) enzyme, which opens up the possibility of new strategies to turn the enzyme “on” to treat cancer or “off” to treat neurodegenerative diseases.
 
PKC is a family of enzymes that controls the activity of other proteins in a cell by attaching chemical tags, which helps determine cell survival or death. When it goes awry, UCSD notes, a number of diseases may result. In a study published August 13 in Cell Reports, researchers at the UCSD School of Medicine reveal what they say is a more accurate structure of PKC, providing new targets for fine-tuning the enzyme’s activity as needed to improve human health.
 
“By understanding how PKC clamps itself closed, we can now look for ways to wedge it open to keep it active,” said Dr. Alexandra C. Newton, a professor of pharmacology. “This has great potential for developing therapies for cancer, in which keeping the enzyme in its ‘on’ position will promote tumor cell death. We also want to do the opposite in neurodegenerative diseases, in which we need treatments that keep neurons alive.”
 
Researchers typically use a technique called X-ray crystallography to determine the 3D structure of proteins, but sometimes they have to make assumptions in order to fit the data together as best they can. In a 2011 study, a different research group resolved most of PKC’s structure and made their best guess at how all the pieces fit together, UCSD explained in a news release.
 
But that structure didn’t add up with the biology of how PKC works, and Newton and her team collaborated with the research team of another professor of pharmacology, Dr. Susan Taylor, to take another look at how to connect the parts, or domains, of the enzyme. They came up with a different structure and tested it using a sophisticated cellular imaging technique to visualize whether PKC was properly packed together or not.
 
The researchers found that PKC’s calcium-sensing (C2) domain interacts with its own tail and enzymatic domain (the part that does the chemical tagging, a process known as phosphorylation), locking the enzyme in an inactive pose. PKC begins to activate when calcium triggers the bridging of the C2 domain to the cell membrane, thus opening the enzyme for activity. The team also validated this packing by mutating specific parts of the protein that hold the domains together, unlocking and relocking PKC between unpacked and correctly packed structures.
 
“Knowing the interfaces that hold PKC closed will now allow the design of small molecules that can either disrupt the interactions between PKC’s domains to open up and activate the enzyme, or clamp the domains closed to prevent its activation,” said first author Dr. Corina Antal, who was a graduate student in Newton’s lab at the time of the study.
 
Regenerating liver tissue without forming tumors
 
Researchers at the UCSD School of Medicine recently discovered a population of liver cells that are better at regenerating liver tissue than ordinary liver cells, or hepatocytes. The study, published August 13 in Cell, is the first to identify these so-called “hybrid hepatocytes,” reportedly showing that they are able to regenerate liver tissue without forming tumors that lead to cancer. The study was done on mouse models, but the researchers also found similar cells in human livers.
 
The team led by Dr. Michael Karin, Distinguished Professor of Pharmacology and Pathology, traced the cells responsible for replenishing hepatocytes following chronic liver injury induced by exposure to carbon tetrachloride, a common environmental toxin. In doing so, they discovered a unique population of hepatocytes located in a specific area of the liver called the portal triad. These special hepatocytes, the researchers found, undergo extensive proliferation and replenish liver mass after chronic liver injuries. Since the cells are similar to normal hepatocytes, but express low levels of bile duct cell-specific genes, the researchers called them “hybrid hepatocytes.”
 
“Although hybrid hepatocytes are not stem cells, thus far they seem to be the most effective in rescuing a diseased liver from complete failure,” said Dr. Joan Font-Burgada, postdoctoral researcher in Karin’s lab and first author of the study.
 
While induced pluripotent stem cells (iPSCs) have shown promise in the area of regenerative medicine, they can continue to proliferate after they’ve done their therapeutic task, which is where cancer risk comes into play. To test the safety of hybrid hepatocytes, Karin’s team examined three different mouse models of liver cancer. They found no signs of hybrid hepatocytes in any of the tumors, leading the researchers to conclude that these cells don’t contribute to liver cancer caused by obesity-induced hepatitis or chemical carcinogens.
 
Epigenetic driver of glioblastoma provides new therapeutic target
 
Cancer’s ability to grow unchecked is often attributed to cancer stem cells, a small fraction of cancer cells that have the capacity to grow and multiply indefinitely. How cancer stem cells retain this property while the bulk of a tumor’s cells do not remains largely unknown. Using human tumor samples and mouse models, researchers at the UCSD School of Medicine and UCSD’s Moores Cancer Center discovered that cancer stem cell properties are determined by epigenetic changes—the chemical modifications cells use to control which genes are turned on or off.
 
The study, published in the Proceedings of the National Academy of Sciences, reported that an enzyme known as lysine-specific demethylase 1 (LSD1) turns off genes required to maintain cancer stem cell properties in the aggressive brain cancer known as glioblastoma, and this epigenetic activity helps explain how glioblastoma can resist treatment. As such, drugs that modify LSD1 levels could provide a new approach to treating glioblastoma.
 
The researchers first noticed that genetically identical glioblastoma cells isolated from patients differed in their tumorigenicity, or capacity to form tumors, when transplanted to mouse models. This observation suggested that epigenetics, rather than genetics, determines tumorigenicity in glioblastoma cancer stem cells, according to UCSD.
 
“One of the most striking findings in our study is that there are dynamic and reversible transitions between tumorigenic and non-tumorigenic states in glioblastoma that are determined by epigenetic regulation,” said senior author Dr. Clark Chen, an associate professor of neurosurgery and vice chair of research and academic development at the UCSD School of Medicine.
 
Probing further, Chen’s team discovered that the epigenetic factor determining whether or not glioblastoma cells can proliferate indefinitely as cancer stem cells is their relative abundance of LSD1. LSD1 removes chemical tags known as methyl groups from DNA, turning off a number of genes required for maintaining cancer stem cell properties, including MYC, SOX2, OLIG2 and POU3F2.
 
“This plasticity represents a mechanism by which glioblastoma develops resistance to therapy,” Chen said. “For instance, glioblastomas can escape the killing effects of a drug targeting MYC by simply shutting it off epigenetically and turning it on after the drug is no longer present. Ultimately, strategies addressing this dynamic interplay will be needed for effective glioblastoma therapy.”
 
Code: E101506

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