Study Findings Could Lead To Treatments In Cancer, Neurological Diseases

Main Category: Cancer / Oncology
Also Included In: Parkinson's Disease;??Huntingtons Disease
Article Date: 08 May 2013 - 0:00 PDT Current ratings for:
Study Findings Could Lead To Treatments In Cancer, Neurological Diseases

Kansas State University scientists helped discover new details about an intricate process in cells. Their finding may advance treatments for cancer and neurological diseases.

Kansas State University researchers Jeroen Roelofs, assistant professor, and Chingakham Ranjit Singh, research assistant professor -- both in the Division of Biology -- led part of the study. Both also are research affiliates with the university's Johnson Cancer Research Center. They worked with colleagues at Harvard Medical School, the University of California-San Francisco and the University of Kansas. The scientific journal Nature recently published the team's observations, titled "Reconfiguration of the proteasome during chaperone-mediated assembly."

The research focused on proteasomes, protein complexes inside the cells of humans and other organisms that help keep the cells healthy.

"The proteasome is a large, molecular machine in the cell that degrades other proteins," Roelofs said. "It's important for protein quality control as well as for the cell's ability quickly remove specific proteins, thereby ensuring the cell's health and proper function."

The goal was to better understand how the various particles inside proteasomes work together to make the proteasomes function -- think the gears and components needed, and in what order, to build a working machine. Scientists believe that disruption of two key particles -- and consequently a proteasome's ability to work correctly -- has implications for cancers as well as various neurological degenerative diseases, such as Parkinson's and Huntington's diseases.

The Nature study built on research that Roelofs made as a postdoctoral research fellow at Harvard Medical School in 2009. He found that proteins called chaperones play a key role in the assembly process of two particles that when connected, gives proteasomes the ability to scrub unwanted proteins from cells. Chaperones act as a foreman for the two particles.

One of the findings in the new study is that in addition to acting as a molecular foreman for the two particles, chaperones also control when those two particles come together. Similarly, the scientists found more about the two particles.

The core particle has seven pockets while the regulatory particle has six tails that tuck into those pockets. When docked together, they turn on the proteasome's functionality.

"In the assembly process there is only one tail that actually determines how the core particle and regulatory particle bind together," Roelofs said. "That's surprising because there are six tails, but only one is needed to give specificity, and the docking into the pocket is controlled by the chaperone."

Roelofs believes that the findings may reveal new targets for anticancer drugs, as a chaperone in the human genes is involved in liver cancer. The proteasome inhibitor Bortezomib is used in the treatment of current cancers. Additionally, the information may advance cancer and neurological research by giving scientists new pathways to study and manipulate.

"This is pretty basic research," Roelofs said. "Understanding the basic mechanics can often lead to new pathways for improvement, which is essential when it comes to human health."

Scientists made the findings through a combination of techniques, including Cryo-electron microscopy, X-ray crystallography, yeast genetics, biochemical reconstitution assays and proteasome activity measurements. These techniques helped researchers observe the submicroscopic tails and complex tail-to-pocket binding process, as well as study the role of the chaperones in the core and regulatory particle process.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. The study was largely funded by the Centers of Biomedical Research Excellence Protein Structure and Function, or COBRE-psf, support center at the University of Kansas -- a multidisciplinary, biomedical research program funded by the National Institute of Health; the Johnson Cancer Research Center at Kansas State University; and the Kansas IDeA Network of Biomedical Research Excellence, or K-INBRE.

Kansas State University

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posted by Gabriel on 8 May 2013 at 8:06 am

On behalf of those who endure Huntington's disease, we give infinite graces to the investigators and to which favor the investigation. Thank you and they continue investigating, we beg it.

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Study Findings May Offer New Way To Kill Cancer Cells By Forcing Them Into An Alternative Programmed Death Pathway

Main Category: Cancer / Oncology
Also Included In: Genetics
Article Date: 16 May 2013 - 1:00 PDT Current ratings for:
Study Findings May Offer New Way To Kill Cancer Cells By Forcing Them Into An Alternative Programmed Death Pathway

When cells suffer too much DNA damage, they are usually forced to undergo programmed cell death, or apoptosis. However, cancer cells often ignore these signals, flourishing even after chemotherapy drugs have ravaged their DNA.

A new finding from MIT researchers may offer a way to overcome that resistance: The team has identified a key protein involved in an alternative death pathway known as programmed necrosis. Drugs that mimic the effects of this protein could push cancer cells that are resistant to apoptosis into necrosis instead.

While apoptosis is a tightly controlled procedure that breaks down and disposes of the dying cell in a very orderly way, necrosis is a messier process in which the cell's membrane ruptures and its contents spill out.

"People really used to think of necrosis as cells just falling apart, that it wasn't programmed and didn't require gene products to make it happen," says Leona Samson, a member of MIT's Center for Environmental Health Sciences and Koch Institute for Integrative Cancer Research. "In the last few years it has become more clear that this is an active process that requires proteins to take place."

In the online edition of the journal Genes and Development, Samson and colleagues report that a protein known as ALKBH7 plays a key role in controlling the programmed necrosis pathway. Dragony Fu, a former postdoc in Samson's lab, is the paper's lead author, and postdoc Jennifer Jordan is also an author.

Unexpected findings

ALKBH7 belongs to a family of proteins first discovered in E. coli about a dozen years ago as part of a DNA-repair mechanism. In humans, there are nine different ALKBH proteins, which Samson's lab has been studying for several years.

Most of the mammalian ALKBH proteins appear to be involved in DNA repair, similar to the original E. coli version. In particular, they respond to DNA damage caused by alkylating agents. These agents can be found in pollutants such as fuel exhaust and tobacco smoke, and are also used to treat cancer.

In the new paper, Samson, a professor of biology and biological engineering, and her colleagues found that ALKBH7 has an unexpected effect. When the researchers lowered ALKBH7 levels in human cells grown in the lab, those cells were much more likely to survive DNA damage than cells with normal ALKBH7 levels. This suggests that ALKBH7 actually promotes cell death.

"That was a surprising finding, because previously all of these ALKBH proteins were shown to be helping the cell survive when exposed to damage," says Fu, who is now a visiting research fellow at the University of Zurich.

Upon further investigation, the researchers found that when healthy cells suffer massive DNA damage from alkylating agents, they enter the programmed necrosis pathway. Necrosis, which can also be initiated by bacterial or viral infection, is believed to help the body's immune system detect threats.

"When dying cells release their contents during necrosis, it serves as a warning signal for your body that there is a virus there and recruits macrophages and other immune cells to the area," Fu says.

Potential drug targets

The findings suggest that when DNA is so badly harmed that cells can't repair it, the programmed necrosis pathway kicks in to prevent cells with major genetic damage from potentially become cancerous.

Other researchers have shown that some types of cancer cells have much lower ALKBH7 levels than normal cells. This suggests that the cancer cells have gained the ability to evade programmed necrosis, helping them to survive, Fu says.

The necrosis pathway appears to be initiated by an enzyme called PARP, which becomes hyperactive following DNA damage and shuts down the cell's production of two molecules that carry energy, ATP and NAD. The MIT team found that ALKBH7 prevents ATP and NAD levels from returning to normal by disrupting the function of mitochondria - the cell structures that generate energy for a cell.

Without an adequate supply of those critical energy-carrying molecules, the cell cannot survive and undergoes necrosis. In cells that lack ALKBH7, ATP and NAD levels rebound, and the cells survive, carrying a heavy burden of DNA damage.

The researchers are now investigating the molecular details of the programmed necrosis pathway in hopes of identifying ways to activate it in cancer cells.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. Written by: Anne Trafton, MIT News Office
The research was funded by the National Institutes of Health and the American Cancer Society.
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'Study Findings May Offer New Way To Kill Cancer Cells By Forcing Them Into An Alternative Programmed Death Pathway'

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