June 6, 2017 First author Angela Arensdorf, Ph.D., and corresponding author Stacey Ogden, Ph.D., an associate member of the St. Jude Department of Cell and Molecular Biology. Credit: Peter Barta / St. Jude Children's Research Hospital

St. Jude Children's Research Hospital molecular biologists have identified an enzyme that activates and "supercharges" cellular machinery that controls how cells become specialized cells in the body.

Malfunction of that machinery, dubbed the Sonic Hedgehog pathway, causes a variety of developmental disorders and cancers, including childhood medulloblastoma and basal cell carcinoma. Researchers believe their basic discovery opens a new research pathway that could lead to drugs to treat such disorders.

Led by Stacey Ogden, Ph.D., an associate member of the St. Jude Department of Cell and Molecular Biology, the research was published June 6 in the journal Cell Reports.

The scientific puzzle the researchers sought to understand was how a major activator of the Sonic Hedgehog pathway, called Smoothened, manages to make its way into an antenna-like cell structure called a "primary cilium," where it communicates with its downstream signaling partners.

Every cell in the body sprouts a primary cilium, which harbors a whole factory of cellular machinery that the cell uses to translate external stimuli into cell responses. Such stimuli include mechanical movement and chemical signals such as hormones. Normally, Smoothened is barred from the primary cilium, keeping the Sonic Hedgehog pathway safely controlled.

In their experiments with cell cultures, the researchers discovered that an enzyme called Phospholipase A2 triggers a mechanism that opens the way for Smoothened movement into the cilium. What's more, the phospholipase triggers an amplification that "supercharges" Smoothened signaling.

"We've basically revealed a new layer of regulation of Smoothened trafficking," Ogden said. "This is a very hot area of research now, because Smoothened trafficking appears to be a very crucial control point for signaling activity. So, if you can change Smoothened trafficking, you can very easily adjust the amplitude of Sonic Hedgehog signaling."

The basic finding has potential clinical importance, Ogden said, because reduced activity in the Sonic Hedgehog pathway is commonly found in genetic disorders of primary cilia function. These disorders include Joubert syndrome, Bardet-Biedl syndrome, Ellis van Creveld syndrome and polycystic kidney diseaseone of the most common genetic diseases in the U.S., affecting more than 600,000 people. Better understanding of the control machinery for the Sonic Hedgehog pathway could lead to more effective therapies for the disorders, Ogden said.

Conversely, hyperactivity of the Sonic Hedgehog pathway is the cause of about 30 percent of childhood medulloblastomas. Medulloblastoma is the most common malignant brain tumor of childhood, accounting for about 20 percent of all childhood brain tumors. Current treatments using surgery, radiation and chemotherapy cause severe side effects, so more precise drug treatments are urgently needed.

"One of the drugs now being used to treat medulloblastoma is a Smoothened inhibitor," Ogden said. "But tumor cells frequently become resistant to this drug and begin to grow again because of mutations in Smoothened that enable it to overcome the drug's inhibition. We want to determine whether drugs to inhibit Phospholipase A2 could reduce Sonic Hedgehog activity in cases where Smoothened becomes insensitive to targeted inhibition."

In adults, Hedgehog pathway hyperactivation also causes basal cell carcinoma, the most common skin cancer and one of the most common cancers. Hedgehog pathway activation also may accelerate other types of tumors by affecting the tissue surrounding the tumor, called the stroma, to create an environment more conducive to growth, Ogden said.

"So Hedgehog pathway inhibitors may be useful in combination therapies with other traditional chemotherapies for other types of solid tumors," she said.

In further research, Ogden and her colleagues are continuing to examine Smoothened regulation and exploring drugs that affect its activity.

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June 6, 2017

The University of Illinois at Chicago College of Medicine will launch a new center that will focus on understanding tissue regeneration and pioneering future developments in stem cell biology as a means to repair diseased organs and tissues.

The center will partner with colleges and departments across the University of Illinois System.

Researchers in the new center will investigate the molecular signals that drive stem cells to mature into different cell types, such as blood, heart and blood vessel cells. The center will also study the epigenetic regulation of stem cells; determine the best approaches to transplant engineered cells, tissues and organs; and look for ways to efficiently produce the regenerative cells needed for novel treatments.

"The center will use a team-oriented multi-disciplinary approach that incorporates experts in biochemistry, biophysics, bioengineering and the clinical sciences to investigate stem cell biology and tissue regeneration," says Asrar Malik, the Schweppe Family Distinguished Professor and head of pharmacology, who is guiding the effort. A search is underway to recruit a director and additional faculty members, he said.

The current program in stem cell biology and regenerative medicine already includes seven faculty members, most within the department of pharmacology, who together have more than $10 million in research grants from the National Institutes of Health. Malik said that the "intent in the next few years will be to carry out additional recruitments with other departments, to build from this interdisciplinary foundation and capitalize on our strengths."

Three new faculty members have joined the center in the last two years. Owen Tamplin studies stem cells in zebrafish; Konstandin Pajcini investigates the role of stem cells in the development of leukemia; and Jae-Won Shin engineers stem cells and tissues with an eye towards transplantation.

This will be the only dedicated stem cell and regenerative medicine center in Chicago with a focus on basic biology and translational science, and will affirm UIC's leadership role in these fields, and help attract additional talent to our team, said Malik.

The opening of the center will be commemorated with a June 12 symposium on stem cell and regenerative medicine from 9 a.m. to 4 p.m. in the Faculty Alumni Lounge, UIC College of Medicine West building, 1853 W. Polk Street.

Speakers include:

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Posted in: Life Sciences News

Tags: Biochemistry, Blood, Blood Vessel, Cell, Epigenetic, Eye, Gene, Genetics, Heart, Heart Disease, Leukemia, Ophthalmology, Pharmacology, Retinal Degeneration, Stem Cell, Transplant, Tumor

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UIC to open new center dedicated for stem cell and regenerative medicine - News-Medical.net

Santa Cruz, CA (Scicasts) The DNA vital to the life of a cell is packaged in chromosomes, and a variety of checkpoints, repair mechanisms, and other cellular safeguards exist to maintain the integrity of the chromosomes during cell growth and division. Those safeguards can fail, however, and a cell may find itself trying to divide into two daughter cells with a loose chromosomal fragment drifting away from a broken chromosome.

William Sullivan calls this a "worst case scenario" for the cell. The potential consequences include cell death or a cancerous cell growing out of control. But Sullivan, a professor of molecular, cell, and developmental biology at UC Santa Cruz, has found that the cell still has one more trick up its sleeve to rescue the broken chromosome.

The latest findings from Sullivan's lab, published in the June 5 issue of Journal of Cell Biology, reveal new aspects of a remarkable mechanism that carries broken chromosomes through the process of cell division so that they can be repaired and function normally in the daughter cells. Sullivan has been studying this process in the fruit fly Drosophila melanogaster. His lab has created a strain of flies in which broken chromosomes are common due to the expression of a DNA-cutting enzyme.

"We have flies in which 80 percent of the cells have double-strand breaks in the DNA, and the flies are fine," he said. "The cell has this amazing mechanism, like a Hail Mary pass with time running out."

The mechanism involves the creation of a DNA tether which acts as a lifeline to keep the broken fragment connected to the chromosome. Powerful new microscopy techniques enable researchers to observe the whole process in living cells, with bright fluorescent tags highlighting the chromosomes and other cellular components.

When a cell divides, it duplicates its chromosomes to make one set for each of the daughter cells. The membrane around the nucleus, which keeps the chromosomes separate from the rest of the cell, breaks down. The two sets of chromosomes then line up and segregate to opposite sides of the cell, pulled apart by a structure of microtubules called the spindle. A new nuclear envelope forms around each set of chromosomes, and new cell membranes separate the two daughter cells.

Sullivan's research has shown that chromosome fragments don't segregate with the rest of the chromosomes, but get pulled in later just before the newly forming nuclear membrane closes. "The DNA tether seems to keep the nuclear envelope from closing, and then the chromosome fragment just glides right in at the last moment," Sullivan said.

If this mechanism fails, however, and the chromosome fragment gets left outside the nucleus, the consequences are dire. The fragment forms a "micronucleus" with its own membrane and becomes prone to extensive rearrangements of its genetic material, which can then be reincorporated into chromosomes during the next cell division. Micronuclei and genetic rearrangements are commonly seen in cancer cells.

"We want to understand the mechanism that keeps that from happening," Sullivan said. "We are currently identifying the genes responsible for generating the DNA tether, which could be promising novel targets for the next generation of cancer therapies."

Sullivan has just received a new four-year, $1.5 million grant from the National Institute of General Medical Sciences to continue this research.

Graduate student Travis Karg is first author of the new paper, which shows that spindle microtubules play an important role in driving the delayed segregation of chromosome fragments. The other coauthors, in addition to Sullivan, are Mary Williard Elting and Sophie Dumont at UC San Francisco and Hannah Vicars at UC Santa Cruz. This work was supported by grants from the National Institutes of Health.

Article adapted from a University of California - Santa Cruz news release.

Publication: The chromokinesin Klp3a and microtubules facilitate acentric chromosome segregation. Travis Karg et al. Journal of Cell Biology (2017): Click here to view.

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'Hail Mary' Mechanism Can Rescue Cells with Severely Damaged Chromosomes, Researchers Say - Scicasts (press release) (blog)