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RESEARCH BRIEFSHIV May Escape Host Cell by Hijacking UbiquitinAs they devise strategies to outwit HIV, AIDS re-searchers are striving to understand the complex nature of the retroviral life cycle. Scientists from the Dana–Farber Cancer Institute now offer new information about a key step. Published in the Nov. 21 PNAS, the study is one of three in the journal to focus on the mechanics of viral departure from cells.
Due to a mutation in the "late domain" of the Gag protein, thousands of HIV molecules sit on the host cell surface, unable to break free. Photo courtesy of Heinrich Gottlinger "The last stages of the formation of viruses within cells and the process by which viruses leave cells are among the least understood aspects of the viral life cycle," said senior author Heinrich Gottlinger, HMS associate professor of pathology at DFCI. "Our research sheds light on previously unknown aspects of this process and on the mechanisms that cause a virus to assemble in the first place." Gottlinger and his group have focused on the "late domain," a key region within the viral Gag protein. This domain is important for final viral assembly before the virus buds from its host cell. Previously, Gottlinger and his colleagues discovered that a strain of HIV lacking the late domain was unable to break free from the cell membrane. As demonstrated through their new study, a proline-rich region within the late domain may serve as a target for cellular proteins that help the virus break free. "We discovered that the late domain attracts cellular machinery that causes proteins called ubiquitin to attach to Gag," said Gottlinger. "This binding enables the buds of virus to leave the cell membrane and spread to other cells." Ubiquitin is known to be important for diverse cellular processes, particularly those that involve breaking down and recycling proteins. Gottlinger hypothesizes that HIV has found a way to corrupt the system and use ubiquitins for its own escape. His lab is now focused on identifying the cellular machinery that binds ubiquitins to the Gag protein. Model of Rare Cancer Shows Gene as Tumor SuppressorA new animal model of a highly lethal cancer found in young children now provides a unique research tool for investigating the genetic basis of the disease. Scientists at HMS, the Dana–Farber Cancer Institute, and Children's Hospital created a mouse model that mimics malignant rhabdoid tumor (MRT). The majority of human cases have a known genetic abnormality, yet current treatments are ineffective. Eighty percent of affected children die, often within one year of diagnosis. Most MRT cases are associated with the inactivation of both copies of the hSNF5 (integrase interactor1) gene. Postdoctoral fellow Charles Roberts and his adviser, Stuart Orkin, chair of pediatric oncology and the David G. Nathan professor of pediatrics at DFCI, who created the murine model, have published findings on the basis of the disorder in the Nov. 28 PNAS Early Edition. The Snf5 protein is a core subunit of the Swi/Snf chromatin-remodeling complex involved in transcriptional activation and repression. Although the genes controlled by Swi/Snf in mammalian cells are unknown, Snf5 is implicated in cancer formation, since it binds to a variety of other proteins, including several oncogenic transcription factors. Through their mouse model, Roberts, Orkin, and their associates found that while a homozygous knockout of Snf5 results in embryonic lethality by day 7, heterozygous mice appear normal at birth. The heterozygotes are not normal, though, since they begin developing tumors consistent with MRT as early as 5 weeks of age. The results point to a role for Snf5 as a tumor suppressor gene. In the heterozygous mice, spontaneous inactivation of the remaining Snf5 allele seems to be required for tumor development. Growth Control Gene Shown Active Across AnimalsA tiny RNA molecule may control developmental timing in creatures as diverse as fish, mollusks, flies, nematodes, and humans. Researchers at HMS and Massachusetts General Hospital originally found this tiny regulatory RNA in C. elegans, but they now have shown it is present and functioning in a wide variety of animals. Earlier this year, Gary Ruvkun, HMS professor of genetics at MGH, and his team discovered the let-7 regulatory RNA and demonstrated that this 21-nucleotide molecule regulates temporal transitions during worm development. The RNA forms a double strand with mRNAs from timing control genes, thereby suppressing their activity. It is believed that the expression of let-7 is necessary to implement the transition from the larval to adult stage. Now, Ruvkun and his colleagues report results from genome sequence searches that detected matches to the let-7 RNA in animals such as annelid worms, mollusks, Drosophila, and humans. They also show that in flies and zebrafish, let-7 is turned on only at late stages of development, just as in C. elegans. Their report, published in the Nov. 2 Nature, points to let-7's potentially universal role in triggering a temporal transition from larval to adult forms in many species. Though humans and other mammals do not have larval stages, their let-7 RNA could regulate transitions such as the molting of baby teeth or the growth of certain tissues at puberty. The let-7 gene is the type that is missed by current methods of genome sequence analysis, Ruvkun explains. That is because let-7 DNA does not code for protein. There are thousands of known genes that encode RNA rather than protein products. In the case of the let-7 regulatory RNA, it was genetic analysis in the worm that identified the gene and comparative analysis of genome sequences that revealed its universality. —Briefs above by Tracy Hampton New Reason to "Sleep on It"School kids may be cutting back on sleep to finish ever mounting piles of homework, but it could be a self-defeating strategy. HMS researchers have found that people who stay up all night after learning and practicing a new task show little improvement in their performance. And no amount of sleep on the following two nights can make up for the toll taken by the initial all-nighter. The research shows "that you need sleep that first night if you want to improve on this task," said Robert Stickgold, HMS assistant professor of psychiatry at the Massachusetts Mental Health Center. The study, which appears in the December Nature Neuroscience, adds a critical piece to a growing body of work by Stickgold and others showing that sleep is necessary for learning (see Focus Oct. 27, 2000). Previously, Stickgold and his colleagues found that people who learned a particular task did not improve their performance when tested later the same day but did improve after a night of sleep. "But this showed us a correlation rather than a causal connection," said Stickgold. To see whether the night of sleep actually caused the improvement, Stickgold trained 24 subjects in the same visual discrimination task, which consisted of identifying the orientation of three diagonal bars flashed for a sixtieth of a second on the lower left quadrant of a computer screen full of horizontal stripes. Half of the subjects went to sleep that night while the other half were kept awake until the second night of the study. Both groups were allowed to sleep on the second and third nights. On the fourth day, both groups were tested on the visual discrimination task. Those who slept the first night identified the correct orientation of the diagonal bars much more rapidly than they had the first day. The other group showed no improvement, despite the two nights of catch-up sleep. "We think that getting that first night's sleep starts the process of memory consolidation," said Stickgold. "So there is a process whereby memories normally wash out of the brain unless some other process nails them down. My suspicion is that sleep is one of those things that does the nailing down." |
