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RESEARCH BRIEFSConjuring with Merlin Opens Way to TherapyNeurofibromatosis type 2 (NF2) is a familial disorder caused by mutations of the NF2 tumor suppressor gene. Those unfortunate enough to carry such mutations are predisposed to tumors of the central nervous system that can lead to blindness, deafness, and other neurological trauma. Though the protein merlin, encoded by the NF2 gene, was identified in the early 90s as a member of a group of cytoskeleton–membrane linkers, breakthroughs in treatment have been lacking largely because the function of this protein is poorly understood.
Two Faces of Merlin. The interaction between the NF2 tumor suppressor, merlin, and the GTPase, Rac, is complex and probably requires the cooperation of several intermediaries. Active, cytoskeleton-bound merlin attenuates Rac-mediated JNK activation and cellular transformation. Rac-induced phosphorylation of merlin, however, inactivates the tumor suppressor and promotes its dissociation from the cytoskeleton. Adapted from original by Andrea McClatchey Some of the mystery surrounding merlin has now been unveiled. HMS assistant professor of pathology Andrea McClatchey, in collaboration with researchers from MIT and the University of North Carolina at Chapel Hill, has demonstrated a link between merlin and Rac, a member of the Rho GTPase family. In July's inaugural issue of Developmental Cell the research team reports that activation of Rac results in phosphorylation of merlin, which weakens binding between its N- and C-terminal ends and thus disrupts its intramolecular bonds. In addition, the cellular localization of merlin is affected by its phosphorylation status; the phosphorylated form is less tightly bound to the actin cytoskeleton. These observations link Rac to tumor development since only hypophosphorylated merlin is known to suppress cell growth. The authors propose that merlin serves to attenuate Rac signaling. Overexpression of merlin inhibits Jun N-terminal kinase (JNK), one of the downstream targets of Rac, and prevents Rac-induced cellular transformation. Furthermore, Nf2-negative cell lines were shown to have higher than normal JNK activity and prominent membrane ruffles—observations consistent with activation of Rac signaling. This pathway now looks like a promising target for developing therapeutic agents. McClatchey points out that Rac is posttranslationally modified by geranylation, the covalent attachment of the 20-carbon geranyl–geranyl moiety. Inhibitors of the enzyme responsible for this modification, geranylgeranyltransferase, could prove beneficial.
How the Firefly Gets Its FlashThe flashing, dancing light show that is the courtship ritual of fireflies has fascinated scientists since its discovery. Though much has been learned about the phenomenon, how these insects (which are actually beetles) regulate their flashing is still not fully understood. Light is emitted from firefly lanterns as the product of an enzymatic reaction—the oxidation of the substrate luciferin by the enzyme luciferase—a reaction that is well understood. What has puzzled researchers for many years, however, is how this reaction is turned on and off quickly enough to produce flashes of light that last only a few hundred milliseconds. One theory is that the reaction is regulated by oxygen supply; O2 is a prerequisite for light production, and it can diffuse quickly enough to elicit the firefly's rapid on–off flashes. New evidence reported in the June 29 Science, however, suggests that a different gas may be involved—nitric oxide (NO). Third-year medical student David Dudzinski and Thomas Michel, HMS associate professor of medicine at Brigham and Women's Hospital, together with colleagues from Tufts University including first author Barry Trimmer, have shown that NO stimulates light production in fireflies. The gas appears to affect the light organs directly, bypassing the central nervous system, since those beetles that had neural connections to their lanterns experimentally severed still glowed under NO. The authors found robust expression of NO synthase in the firefly lanterns and could show that flashes stimulated by the neurotransmitter octopamine are attenuated by NO scavengers, chemicals that rapidly destroy the gas. The O2 link is not totally broken, however. The authors suggest a novel mechanism of action for NO, that it acts to reduce the rate of mitochon-drial respiration, possibly by inhibiting cytochrome oxidase, thus leading to a transient increase in levels of O2.
Link Made Between Proteins Associated with Parkinson'sThe tremors and muscle rigidity that are symptomatic of Parkinson's disease are largely due to neurodegeneration in a specific part of the brain, the substantia nigra. But the molecular basis for this cellular blight remains hidden. In conventional, or idiopathic Parkinson's, genetic predisposition and environmental factors may contribute to the disease, making the etiology difficult to pinpoint. Instead, clues may come from the study of rare familial forms of the disease where mutations in specific genes have been discovered. Two such genes encode the proteins alpha-synuclein and parkin. Alpha-synuclein is found in diseased neurons within large protein aggregates called Lewy bodies; whether these inclusions are beneficial or detrimental to neurons is hotly debated. Parkin is a ubiquitin ligase, capable of marking protein substrates for degradation by covalently tagging them with ubiquitin. The obvious conclusion is tempting to make: parkin's role is to tag alpha-synuclein for degradation. When this process goes awry alpha-synuclein accumulates. Direct evidence for this has been lacking, however, until now. Hideki Shimura, research fellow in neurology, and Michael Schlossmacher, instructor in neurology, working in the laboratories of Kenneth Kosik, professor of neurology, and Dennis Selkoe, the Vincent and Stella Coates professor of neurologic diseases, at the Center for Neurological Diseases, Brigham and Women's Hospital, have demonstrated a link between these two proteins. Their report, published in the July 12 Science, shows that alpha-synuclein not only colocalizes with parkin, but it can be ubiquitinated by the ligase. Furthermore, point mutations in either the substrate-binding domain or the ubiquitin-conjugating domain of parkin abolish its ligase activity. In a surprising twist, however, parkin was found to recognize a heretofore uncharacterized form of alpha-synuclein, one that is posttranslationally modified by glycosylation. The authors found that the modified synuclein is elevated in brains of patients suffering from parkin-deficient Parkinson's and are now focusing on its role in the idiopathic form of the disease.
Breast Cancer Protection Gained Through Loss of Cell Division ProteinFor years scientists have sought a "magic bullet" for cancer—a therapy that would attack only tumor cells and leave noncancerous cells unscathed. The prerequisite for such a strategy is a molecular target, be it gene or protein, that is essential for tumor growth but dispensable in all other cells. In the case of breast cancer, the second most common form among women in the U.S., researchers at the Dana–Farber Cancer Institute may have found such a target, the cell division cyclin D1. A pivotal role for the D1 gene in breast cancer has long been suspected; D1 protein levels are elevated in more than 50 percent of human mammary carcinomas and transgenic mice overexpressing the protein are highly susceptible to developing such tumors. Now, in a series of experiments reported in the June 28 Nature, Qunyan Yu and Yan Geng, working in the laboratory of HMS assistant professor of pathology Piotr Sicinski, show that in mice, loss of the D1 protein protects against breast cancer. The researchers crossed D1 knockout mice with mates harboring the breast-cancer–inducing oncogenes v-Ha-Ras, c-Neu, c-Myc , and Wnt-1. Though D1 knockouts expressing the Myc or Wnt-1 gene developed almost as many tumors as mice expressing D1, the researchers failed to detect a single tumor in D1 knockouts expressing Ras or Neu. Furthermore, the protection offered by ablation of the D1 gene was restricted to breast tissue. The gene's absence failed to protect transgenic mice from Ras-induced salivary gland tumors, and D1 knockout fibroblasts expressing the Ras or Neu oncogenes readily formed tumors in nude mice. The results suggest that inhibition of D1 may prove to be an effective and selective method of fighting breast cancer. —Briefs by Tom Fagan |
