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Protein's Essential Role in Repairing Damaged Cells Revealed U-M scientistshave identified a target that may predict tumors' sensitivity to radiation. University of Michigan researchers have discovered that a key protein in cells plays a critical role in not one, but two processes affecting the development of cancer. "Most proteins involved in responding to DNA damage that can cause cancer either help detect the damage and warn the rest of the cell, or help repair the damage," says David O. Ferguson, M.D., Ph.D., the study's lead author. Ferguson is an assistant professor of pathology at the U-M Medical School and a member of U-M's Comprehensive Cancer Center. Prior research has shown that the protein, Mre11, functioned as a "gatekeeper" to signal injury to the cell and prevent damaged cells from proliferating. Now, Ferguson and colleagues have discovered that in mammals, a function of the Mre11 protein also serves as a "caretaker," by repairing DNA. Their findings, published in the journal Cell, could have important implications for cancer treatment by someday allowing oncologists to predict a tumor's sensitivity to radiation and other therapies, making it more vulnerable to treatment. Under normal circumstances, the body's cells grow, divide and eventually die. When something damages a healthy cell's DNA -- such as radiation or exposure to a toxin -- a multiprotein complex steps in to repair the breakage and activate other fundamental cellular processes. The MRN complex, comprised of the Mre11, Rad50 and NBS1 proteins, senses DNA damage, known as double-strand breaks, within the cell. The complex then transmits that information to an enzyme called the ATM (ataxia-telangiectasia mutated) checkpoint kinase. The ATM kinase controls the cell's response to double-strand breaks, and slows cell growth to give the cell opportunities to repair them, says Ferguson. When the MRN complex doesn't work properly, inherited human neurological diseases, such as ataxia-telangiectasia-like syndrome and Nijmegen breakage syndrome, result. Both feature MRN mutations and significantly predispose a person to immunodeficiency and cancer. What Ferguson and colleagues discovered is that Mre11 not only senses and communicates damage, it also repairs DNA double-strand breaks by acting as a nuclease, an enzyme that modifies and processes the broken DNA ends. Research details The researchers generated mouse models to examine the exact role of Mre11 in the MRN complex. They engineered two mouse strains, one in which Mre11 was disabled completely, and one in which only a single amino acid change was made. What surprised researchers the most was that making that change to a single amino acid in Mre11 caused consequences as severe as when they eliminated the entire MRN complex. Taking out the amino acid in Mre11 responsible for nuclease activity caused the mice to develop growth defects, chromosomal abnormalities and sensitivity to DNA-damaging agents. Therefore, researchers could say that the nuclease, or repair, activity of Mre11 proves critical for both MRN function and stability of the genetic material of the organism. “First, Mre11 signals to the cell by activating the kinase, but it also acts in the repair of double-strand breaks via the nuclease functions. Therefore, it prevents the two individual steps that lead to cancer," Ferguson says. Implications The work, called "virtuoso cell engineering" in a Cell preview article, holds particular promise for identifying mutations associated with many cancers. "What's emerging in the literature from large-scale screening studies of human tumors is that Mre11 may be frequently mutated in certain cancers," Ferguson says. "This may have implications for diagnoses because tumors associated with different mutations may have different prognoses and respond to different therapies," he says. In particular, mutations in Mre11 may predict how sensitive or resistant a particular tumor will be to treatments with DNA-damaging agents. “The fact that we have now separated the functions of DNA repair from the checkpoint functions means we may have identified a target that can sensitize tumors to radiation and chemotherapeutic agents used in treating cancer."
MIT Researchers Find New Way to Fuse Cells Fusing cells together is crucial in analyzing the way their internal structure and DNA reprogram themselves after merger, and may hold the key to obtaining successful cellular hybrids between adult cells and stem cells. This can provide new stem cell treatments for conditions requiring such intervention. But technical difficulties encountered by the fuse process only placed its success rate at about 10 percent. Now, researchers at the Massachusetts Institute of Technology managed to devise a way of combining the cells that increase the success rate from 10 to more than 50 percent. The new study, published online January 4th in Nature Methods, was led by associate professor of electrical engineering and computer science Joel Voldman and professor of biology Rudolf Jaenisch, who is also a Whitehead Institute member. In other methods, streams of different cells, A and B, were made to flow on a tiny chip, which had small cups attached to it. These cups were only able to hold two cells, but the main flaw of these systems was the fact that there was no way to control how the cells paired up. In the end, many cups held cells of the same type, either AA or BB. The number of desired combinations (AB) was only 1 in 10. With the new system, only A cells are made to flow in cups, this time smaller, and only able to hold one cell. After most cells are thus trapped, they are made to flow the other way around, in larger cups, situated opposite of the small ones. B cells are then made to flow in the large cups, thus increasing the chance of them meeting A cells. Once most cells are paired up, an electrical impulse fuses their membranes together. Besides stem cell reprogramming, this technique could also be used to study interactions between any type of cells, be they animal or human. The applications for this research are limitless and drastically reduce the amount of time spent by researchers in labs worldwide. |
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Neuroblastoma cells are derived from migratory neural crest cells that give rise to the peripheral sympathetic nervous system. During normal development, neural crest cells stop dividing and differentiate. However, neuroblastoma cells seem to have lost this capacity. Previous work has shown that amplification of the MYCN gene, which disrupts control of cell division and differentiation, is a strong predictor of poor prognosis in neuroblastoma.
"We speculated that genes that are expressed in a MYCN-dependent manner might be required specifically for the growth of MYCN-amplified neuroblastomas and that MYCN-amplified neuroblastomas might depend not only on N-Myc itself, but also on upstream regulatory factors or downstream target genes," explains senior study author, Dr. Martin Eilers, from the University of Wurzburg in Germany.
Dr. Eilers and colleagues performed a genetic screen of nearly 200 genes that are dependent on amplified MYCN in human neuroblastoma or are direct targets of Myc. The researchers found that the oncogene AURKA is required for growth of MYCN-amplified neuroblastoma cells, but not cells lacking amplified MYCN.
AURKA encodes the kinase Aurora A which is dysregulated in multiple types of cancer cells. Interestingly, Aurora A kinase activity was not required for N-Myc stabilization. Instead, elevated Aurora A levels in MYCN-amplified neuroblastoma cells interfered with the PI3-kinase-dependent and mitosis-specific degradation of N-Myc. This suggests that small molecule inhibitors of Aurora A kinase may not be effective at inhibiting the oncogenic functions of Aurora A.
"Our results show that stabilization of N-Myc is a critical oncogenic function of Aurora A in childhood neuroblastoma; the challenge will now be to find ways to interfere with this function in order to find new approaches for the therapy of these tumors," says Dr. Eilers. "The findings also suggest that the current views about why Aurora A is oncogenic may need to be re-evaluated."
A Protein that Protects Against Alzheimer's?
The discovery has aroused considerable interest among the molecular biology community.
Research on the mechanisms involved in neurodegenerative diseases such as Alzheimer's, stroke, dementia, Parkinson's and multiple sclerosis, to name a few, has taken a step forward thanks to the work of biological sciences Ph.D. student Sonia Do Carmo, supervised by Professor Eric Rassart of the Universite du Quebec a Montreal (UQAM) Biological Sciences Department, in collaboration with researchers at the Armand-Frappier Institute and the University of Valladolid in Spain.
Do Carmo and her collaborators have successfully demonstrated the protective and reparative role of apolipoprotein D, or ApoD, in neurodegenerative diseases. Their discovery suggests interesting avenues for preventing and slowing the progression of this type of illness.
These studies were inspired by work done ten years ago by Professor Rassart's team, who then discovered increased levels of ApoD in the brains of people with several types of neurodegenerative disorders, including Alzheimer's. The team hypothesized that this protein might play a protective and restorative role but were unable to demonstrate this at the time.
The experiments
To establish the protective and reparative role of ApoD, the researchers used two types of genetically modified mice: one type with increased levels of ApoD in the brain and a second type with no ApoD. The mice were then exposed to neurodegenerative agents. A group of the modified mice and a control group (unmodified) were exposed to paraquat, a widely used herbicide that has been shown to increase the risk of Parkinson's. Then the same type of experiment was performed by injecting two groups with a virus that causes encephalitis. In both cases, the mice modified for increased levels of ApoD had the best outcomes, with a better ability to combat the diseases and a higher survival rate than the unmodified mice. The knockout mice with no ApoD displayed the poorest outcomes. These experiments serve to illustrate the protective and reparative role of this protein.
When can we expect medication?
A number of steps remain before this research can translate into effective drugs against neurodegenerative conditions. The original investigator, Professor Eric Rassart, explains, "You cannot simply inject ApoD, as it has to enter the brain in order for it to be active. We have successfully demonstrated the role of ApoD, but now we need to understand the action of this protein. Only then will we be able to think about creating a drug to prevent these types of diseases and to slow their progression. All the same, this discovery by Sonia Do Carmo and her collaborators is a significant breakthrough, as we know very little about the mechanisms of neurodegenerative diseases."

A 'Scrawny' Gene Keeps Stem Cells Healthy
Researchers observed the effects of scrawny on every major type of stem cell found in fruit flies ... mutant flies without functioning copies of the scrawny prematurely lost their stem cells in reproductive tissue, skin, and intestinal tissue.
Stem cells are the body's primal cells, retaining the youthful ability to develop into more specialized types of cells over many cycles of cell division. How do they do it? Scientists at the Carnegie Institution have identified a gene, named scrawny, that appears to be a key factor in keeping a variety of stem cells in their undifferentiated state. Understanding how stem cells maintain their potency has implications both for our knowledge of basic biology and also for medical applications. The results will be published in the January 9, 2009 print edition of Science.
"Our tissues and indeed our very lives depend on the continuous functioning of stem cells," says Allan C. Spradling, director of the Carnegie Institution's Department of Embryology. "Yet we know little about the genes and molecular pathways that keep stem cells from turning into regular tissue cells—a process known as differentiation."
In the study, Spradling, with colleagues Michael Buszczak and Shelley Paterno, determined that the fruit fly gene scrawny (so named because of the appearance of mutant adult flies) modifies a specific chromosomal protein, histone H2B, used by cells to package DNA into chromosomes. By controlling the proteins that wrap the genes, scrawny can silence genes that would otherwise cause a generalized cell to differentiate into a specific type of cell, such as a skin or intestinal cell.
The researchers observed the effects of scrawny on every major type of stem cell found in fruit flies. In the experiments, mutant flies without functioning copies of the scrawny prematurely lost their stem cells in reproductive tissue, skin, and intestinal tissue.
Stem cells function as a repair system for the body. They maintain healthy tissues and organs by producing new cells to replenish dying cells and rebuild damaged tissues. "Losing stem cells represents the cellular equivalent of eating the seed corn," says Spradling.
While the scrawny gene has so far only been identified in fruit flies, very similar genes that may carry out the same function are known to be present in all multicellular organisms, including humans. The results of this study are an important step forward in stem cell research. "This new understanding of the role played by scrawny may make it easier to expand stem cell populations in culture, and to direct stem cell differentiation in desired directions," says Spradling.
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