2 Genes Play Crucial Role in Embryonic Cell Survival

2 Genes Play Crucial Role in Embryonic Cell Survival Tuesday, 05 February 2008 New research suggests that two recently discovered genes are critically important for controlling cell survival during embryonic development. The genes, called E2F7 and E2F8, are the least understood members of a family of genes that play a fundamental role in animal development. Members of this family are also involved in cancers of the breast, bladder, stomach and colon. This animal study showed that complete loss of the two genes causes massive cell death and is lethal in developing embryos. It also showed that the two genes prevent this cell death largely by suppressing the activity of another member of the family, called E2f1. This third gene is known to play an important role in triggering programmed cell death, or apoptosis, in embryos. The findings by researchers at the Ohio State University Comprehensive Cancer Center are published in the Jan. 15 issue of the journal Developmental Cell, with an accompanying commentary. “Until now, almost nothing was known about the function of these two genes in animals,” says principal investigator Gustavo Leone, an associate professor of molecular virology, immunology and medical genetics at Ohio State’s Comprehensive Cancer Center. “Our study not only shows that both these genes are critical for embryonic development, but also how members of this gene family work together to regulate cell survival and proliferation.” Leone and his colleagues used mice that were missing either E2f7 or E2f8, or both genes, and mice missing both genes and the E2f1 gene. Their experiments showed that embryos survived, and massive cell death was prevented, if they had at least one copy (of the normal two) of either of the two genes. When the two genes were entirely missing, however, massive cell death and other problems occurred that were lethal before birth. On the other hand, embryos that were completely missing both genes and missing the E2f1 gene, did not show the massive cell death, although they also died before birth. “This of course means that E2f7 and E2f8 are doing more than just regulating cell death, and we are now exploring new avenues of their function,” Leone says. “Overall,” he says, “our findings indicate that these two genes are essential for embryonic development and for preventing widespread cell death, mainly by targeting the E2f1 gene.” Reference: Synergistic Function of E2F7 and E2F8 Is Essential for Cell Survival and Embryonic Development Developmental Cell, Vol 14, 62-75, 15 January 2008 ......... ZenMaster

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China’s new Great Leap Forward — in drug discovery

China’s new Great Leap Forward — in drug discovery Monday, 04 February 2008 In a modern-day counterpart to Mao Zedong’s program to modernize the Chinese economy, China’s pharmaceutical industry is quietly taking its own Great Leap Forward — as a major force in drug discovery and development, according to an article scheduled for the Feb. 4 issue of Chemical & Engineering News, ACS’ weekly newsmagazine. China already is an important source of active ingredients that large pharmaceutical companies in the United States and other countries use to make prescription and over-the-counter drugs Chemical & Engineering News’s cover story, by Senior Correspondent Jean-François Tremblay, notes that China is playing an increasingly important, yet mostly unrecognized role in drug discovery. Companies based in China that undertake research projects on behalf of foreign companies have in the past three years beefed up their range of services. From Shanghai to Beijing, new companies are being launched with research capabilities that, in terms of the time it takes to produce results, exceed those of Western pharmaceutical companies. A growing number of Chinese firms offer a full range of drug research and development services, including synthesis, process research and scale up, and animal testing, the article states. Within two years, the first drug to be mostly developed in China could begin human trials in the U.S., Tremblay says. The growth in pharmaceutical services in China seems to be part of a major trend. “Last century, we saw the pharmaceutical industry move from Europe to the United States,” Chemical & Engineering News quotes a manager at one drug discovery company. “Now, it’s perhaps moving to China and India.” Article: China’s Pharma Leaps into Discovery Chemical & Engineering News ......... ZenMaster

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Targeting astrocytes slows disease progression in ALS

Targeting astrocytes slows disease progression in ALS Sunday, 03 February 2008 In what the researchers say could be promising news in the quest to find a therapy to slow the progression of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, scientists at the University of California, San Diego (UCSD) School of Medicine have shown that targeting neuronal support cells called astrocytes sharply slows disease progression in mice. The study, conducted in the laboratory of Don Cleveland, Ph.D., UCSD Professor of Medicine, Neurosciences and Cellular and Molecular Medicine and member of the Ludwig Institute for Cancer Research, will appear in the advance online publication on Nature Neuroscience's website on February 3rd. “Mutant genes that cause ALS are expressed widely, not just in the motor neurons,” Cleveland explained. “Targeting the partner cells like astrocytes, which live in a synergistic environment with the neuron cells, helps stop the ‘cascade of damage.’ Therapeutically, this is the big news.” ALS is a progressive disease that attacks the motor neurons, long and complex nerve cells that reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body, which act to control voluntary movement. Degeneration of the motor neurons in ALS leads to progressive loss of muscle control, paralysis and untimely death. Estimated to affect some 30,000 Americans, most people are diagnosed with ALS between the ages of 45 and 65. Typically, ALS patients live only one to five years after initial diagnosis. In findings published in Science in June 2006, Cleveland and his colleagues showed that in early stages of inherited ALS, small immune cells called microglia are damaged by mutations in the SOD1 protein, and that these immune cells then act to significantly accelerate the degeneration of the motor neurons. The new study demonstrates that much the same thing happens to astrocytes, support cells that are essential to neuronal function, and whose dysfunction is implicated in many diseases. The researchers speculate that the non-neuronal cells play a vital role in nourishing the motor neurons and in scavenging toxins from the cellular environment. As with microglia, the helper role of astrocytes is altered due to mutations in the SOD1 protein. “We tested what would happen if we removed the mutant gene from astrocytes in mouse models,” said Cleveland. “What happened was it doubled the lifespan of the mouse after the onset of ALS.” Astrocytes are key components in balancing the neurotransmitter signals that neurons use to communicate. To examine whether mutant SOD1 damage to the astrocytes contributes to disease progression in ALS, researchers in the Cleveland lab used a genetic trick to excise the mutant SOD1 gene, but only in astrocytes. Reduction of the disease-causing mutant SOD1 in astrocytes did not slow disease onset or early disease; however, the late stage of the disease was extended, nearly doubling the normal life expectancy of a mouse with ALS. “Silencing the mutant gene in the astrocytes not only helps protect the motor neuron, but delays activation of mutant microglia that act to accelerate the progression of ALS,” said Cleveland. The findings show that mutant astrocytes are likely to be viable targets to slow the rate of disease spread and extend the life of patients with ALS. Cleveland added that this may prove especially important news to researchers in California and elsewhere working with stem cells. “This gives scientists a good idea of what cells should be replaced using stem cell therapy. Astrocytes are very likely much easier to replace than the slow-growing motor neuron.” Additional contributors to the study include Koji Yamanaka, Seung Joo Chun and Severine Boillee, Ludwig Institute for Cancer Research and UCSD Department of Medicine and Neuroscience; Noriko Fujimore-Tonou and Hirofumi Yamashita, Yamanaka Research Unit, RIKEN Brain Science Institute, Saitama, Japan; David H. Gutmann, Department of Neurology, Washington University, St. Louis; Ryosuke Takahashi, Department of Neurology, Kyoto University, Japan; and Hidemi Misawa, Department of Pharmacology, Kyoritsu University of Pharmacy, Tokyo. ......... ZenMaster

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