Tracing the pathways of neurofibromatosisJanuary 19, 2007Michael Stern's latest research into the formation of neurofibromatosis tumors reads something like a federal racketeering indictment, except that Stern's tracing proteins instead of laundered money, and he's looking not at offshore accounts but at biochemical paths of cause and effect. The research, which appears in the Jan. 10 issue of the Journal of Neuroscience, seeks to find the biochemical pathway that's responsible for tumors in people with the genetic disorder neurofibromatosis. Stern built his case much like a prosecutor, compiling evidence from dozens of painstaking experiments on mutant fruit flies, each with a specific genetic flaw that testified to the power of one or more proteins involved. Neurofibromatosis is characterized by the formation of tumors of peripheral nerve cells. Scientists know the disease is caused by defects in a gene called Nf1, but they have yet to find out precisely how the defective genes cause tumors to form. "Our results suggest that having a defect in Nf1 begins a kind of biochemical domino effect that eventually leads to tumor growth," said Stern, professor of biochemistry and cell biology. Stern's research group used fruit flies for several reasons: the insect's genome has been sequenced; it takes only two weeks to grow an new generation of fruit flies; and scientists know which fruit fly genes are analogous to the human genes associated with neurofibromatosis. In preparing for its experiments, Stern's group knew that Nf1 encodes a protein called neurofibromin that inhibits the effect of a second protein called Ras, which is known to promote nerve cell growth. They also knew that a third protein called PI3K was recently reported to be hyperactivated in mice that had defective Nf1 genes, and they knew that PI3K requires the activity of a fourth protein called Akt, to carry out its tasks. In their experiments, they created more than two dozen mutant strains of fruit flies, including varieties that were either missing the genes to make one of the four proteins or were encoded to overexpress, or make extra amounts of, one of the four. Some mutants were designed to carry more than one defective trait. Nerves from each mutant strain were examined. By comparing the mutant strains - each with a specific defect or set of defects - they buillt a case that the absence of neurofibromin allows Ras, PI3K and Akt to work in concert to inhibit a regulatory group of proteins called 'forkhead box O,' or FOXO. FOXO proteins are key players in regulating the genes responsible for programmed cell death and DNA repair - two common culprits in cancer. "Our results raise the possibility that neurofibroma formation in individuals with neurofibromatosis might result in part from a Ras-PI3K-Akt-dependent inhibition of FOXO," Stern said. Stern said the project required an enormous amount of work in the lab, and it wouldn't have been possible without the dedication and motivation of research technician Willliam Lavery, the paper's first author. "Will displayed terrific leadership on this project," Stern said. Rice University |
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| Related Neurofibromatosis Current Events and Neurofibromatosis News Articles Loss of tumor supressor gene essential to transforming benign nerve tumors into cancers Researchers at UCLA's Jonsson Comprehensive Cancer Center showed for the first time that the loss or decreased expression of the tumor suppressor gene PTEN plays a central role in the malignant transformation of benign nerve tumors called neurofibromas into a malignant and extremely deadly form of sarcoma. New research strategy for understanding drug resistance in leukemia UCSF researchers have developed a new approach to identify specific genes that influence how cancer cells respond to drugs and how they become resistant. This strategy, which involves producing diverse genetic mutations that result in leukemia and associating specific mutations with treatment outcomes, will enable researchers to better understand how drug resistance occurs in leukemia and other cancers, and has important long-term implications for the development of more effective therapies. Anti-angiogenesis treatment improves hearing in some NF2 patients Treatment with the angiogenesis inhibitor bevacizumab improved hearing and alleviated other symptoms in patients with neurofibromatosis type 2 (NF2). Chromosomal problems affect nearly all human embryos For the first time, scientists have shown that chromosomal abnormalities are present in more than 90% of IVF embryos, even those produced by young, fertile couples. Rice University study finds possible clues to epilepsy, autism Rice University researchers have found a potential clue to the roots of epilepsy, autism, schizophrenia and other neurological disorders. Mapping a clan of mobile selfish genes Much of human DNA is the genetic equivalent of e-mail spam: short repeated sequences that have no obvious function other than making more of themselves. Pediatric study finds alternatives for radiation of low-grade brain tumors A multi-institutional study led by researchers at The University of Texas M. D. Anderson Cancer Center has found that using chemotherapy alone and delaying or avoiding cranial radiation altogether can be effective in treating pediatric patients with unresectable or progressive low-grade glioma. Anti-cancer drug prevents, reverses cardiovascular damage in mouse model of premature aging disorder An experimental anti-cancer drug can prevent -- and even reverse -- potentially fatal cardiovascular damage in a mouse model of progeria, a rare genetic disorder that causes the most dramatic form of human premature aging, National Institutes of Health (NIH) researchers reported today. Gene's newly explained effect on height may change tumor disorder treatment A mutation that causes a childhood tumor syndrome also impairs growth hormone secretion, researchers at Washington University School of Medicine in St. Louis have found. Protein key to neuro-regeneration Researchers at the Peninsula Medical School in the South West of England, University College London, the San Raffaele Scientific Institute in Milan and Cancer Research UK, have for the first time identified a protein that is key to the regeneration of damage in the peripheral nervous system and which could with further research lead to understanding diseases of our peripheral nervous systems and provide clues to methods of repairing damage in the central nervous system. More Neurofibromatosis Current Events and Neurofibromatosis News Articles |
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