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New Function Discovered For Heat Shock ProteinAlexzander Asea and Stuart Calderwood have coined a new term—"chaperokine"—for heat shock protein 70 (hsp70). It seems the well known molecular chaperone can second as a cytokine, signaling a potent inflammatory response in monocytes. The Dana–Farber researchers and their colleagues are the first to report the new role for hsp70, and their findings appear in the April Nature Medicine. Recognized many years ago for its ability to bind to and protect proteins from denaturation after an increase in body temperature, hsp70 also shields proteins from a number of other environmental, physiologic, and pathogenic assaults. The protein and its heat shock family members have been highly conserved in evolution. Both prokaryotes and eukaryotes are equipped with the protective chaperones. After reviewing the available evidence, the researchers began to suspect that hsp70 might wear another hat. They hypothesized that since it is highly expressed during an infection, hsp70 might not only protect proteins from microbes within cells but might also be secreted, signaling an alarm to the immune system.
Heat shock protein 70 (hsp70) binds to monocytes (white), causing the release of pro-inflammatory mediators TNF alpha, IL-6, and IL-1 beta. The ability of hsp70 to function as a cytokine was not previously known. Image courtesy of Stuart Calderwood Asea, HMS instructor in radiation oncology and lead author of the study, first determined whether hsp70 could bind to the surface of monocytes, one of the first cells to respond to an infection. Not only did it bind (see figure), but it also provoked the cells to release pro-inflammatory mediators, including tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6. Asea and principal investigator Calderwood, HMS associate professor of radiation oncology, are primarily interested in cancer immunotherapy. It is known that heat shock proteins can be used as adjuvants—large molecules to which small molecules, such as tumor antigens, are attached in order to mount a more effective immune response. The researchers are enthusiastic about hsp70's new role since while functioning as an adjuvant, it could also help the immune system destroy tumors. Interested in the prospect of using heat shock proteins as therapeutic tools in a variety of diseases, they have organized a symposium to be held in November in Woods Hole, which will bring together scientists from many fields. Study Elucidates How Protein Complex Controls TranscriptionNucleosomes, consisting of DNA wrapped around histone proteins, are able to repress gene transcription by blocking the access of transcription factors. Certain protein complexes can relieve this repression by altering the nucleosome's structure so transcription factors can bind and activate their respective genes. Now researchers in the lab of Fred Winston, HMS professor of genetics, report new information about the genes controlled by one such complex, Snf/Swi. Although scientists knew the conserved yeast multiprotein complex affects transcription by nucleosome remodeling, little was known about its genomewide effects, including whether Snf/Swi affects individual genes in various locations, or genes clustered together in specific chromosomal domains. Using whole genome expression analysis, Priya Sudarsanam, a graduate student (currently an HMS research fellow), Winston, and collaborators at Stanford Medical School discovered that Snf/Swi alters the transcription of many genes scattered throughout the genome. One of these is the MCM1 gene, which expresses an essential transcription factor involved in many cellular processes. The researchers also learned that Snf/Swi can repress transcription. Their experiments suggest the repression is direct and mechanistically separate from the complex's role in activation. Sudarsanam is the lead author of the study, which appears in the March 28 Proceedings of the National Academy of Sciences. Stress Response Pathway Identified In PlantsA group of Massachusetts General Hospital researchers report they have identified master genes that protect plants from a variety of environmental stresses. Plants accumulate large amounts of hydrogen peroxide (H2O2) after they are stressed by cold, heat, drought, wounds, pathogens, salinity, and other unfavorable conditions. Its production somehow triggers pathways that turn on genes that help defend the plant, although the molecules in that pathway have never been identified. Working with Arabidopsis, a member of the mustard family, the researchers discovered that H2O2 activates Arabidopsis NPK1-like protein kinase (ANP1), which then initiates a phosphorylation cascade involving mitogen activated protein kinases (MAPKs), causing the activation of stress-responsive genes. Some of these genes code for heat shock proteins and detoxification enzymes. The researchers also discovered that H2O2 blocked the action of a plant growth hormone, auxin. They believe that by switching off auxin-mediated activities, the plant is less vulnerable and is able to conserve more energy for stress protection. Significantly, tobacco plants overexpressing an ANP1 homologue, NPK1, were better able to tolerate heat, freezing, drought and high salt conditions. Thus, the researchers believe that manipulation of the ANP1/NPK1 gene in plants might be beneficial in agriculture. According to the study's leader, Jen Sheen, HMS associate professor of genetics, "In the past, people expressed individual target genes to gain minor protection to limited stress conditions. We showed that ANP1/NPK1 are master genes that turn on many genes and can enhance plant tolerance to multiple and diverse stress conditions such as freezing and heat stress." Yelena Kovtun, a former HMS research fellow, is the first author of the study, which appears in the March 14 Proceedings of the National Academy of Sciences. Protein Pair Positions Mitotic SpindleCorrect positioning of the mitotic spindle is critical for cell division. Yet no one knows exactly what mechanisms allow it to position itself properly. Now a group of Dana–Farber researchers have added a major piece to the puzzle. They have discovered that a protein in yeast, Bim1p, which sits on the ends of the microtubules that make up the spindle, binds to Kar9p, a protein located in the cell cortex—a region just inside the cell membrane. Binding of the two proteins fixes the spindle in place. Although it was known that microtubules attach to the cell cortex while positioning the mitotic spindle, the proteins that actually make the connection had not been identified. The discovery builds on previous work from the lab of David Pellman, HMS assistant professor of pediatrics. Pellman's group has been interested in the mechanisms of mitotic spindle positioning and its significance for asymmetric cell division. Often, particularly during development, different parts of a cell are donated to daughter cells during mitosis. The daughters, possessing dissimilar complements of proteins, RNA, and other molecules, then embark on different developmental pathways. The location of the mitotic spindle in the original cell solely dictates where it will divide and therefore what parts of it will be donated to each daughter. The use of budding yeast provided the researchers with an ideal model of asymmetric cell division, as well as a simple system to study mitotic spindle positioning. Their findings will likely be applicable to other eukaryotic cells as well. For example, Bim1p is a member of the human EB1 family of proteins, which Pellman's lab also studies. Like Bim1p, EB1 binds to microtubule ends. Interestingly, EB1 also interacts with the adenomatous polyposis coli (APC) tumor suppressor protein, which is implicated in colon cancer. And the region of APC that is deleted in colon cancer is the one that binds to EB1. So EB1 may be important not only for spindle positioning, but also for cancer biology. Pellman's group is interested in finding the connection between these two functions. Laifong Lee, a graduate student from Princeton University, is the first author of the study, published in the March 24 Science. —Briefs by Lorene Leiter |
