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Cancer gene discovery has relied extensively on analyzing tumors for gains and losses to reveal the location of oncogenes and tumor suppressor genes, respectively. Deletions of 1p36 are extremely common genetic lesions in human cancer, occurring in malignancies of epithelial, neural, and hematopoietic origin. Although this suggests that 1p36 harbors a gene that drives tumorigenesis when inactivated,...
Philanthropists are exerting an unmistakable influence on the research agenda, drawing attention to long-ignored research areas, promoting collaborations, and giving scientists the freedom to explore serendipitous ideas. Unbridled by politics or bureaucracy, philanthropic organizations can fund the riskier projects that could yield the biggest payoffs.
Kinetochores of sister chromatids attach to microtubules emanating from the same pole (coorientation) during meiosis I and microtubules emanating from opposite poles (biorientation) during meiosis II. We find that the Aurora B kinase Ipl1 regulates kinetochore-microtubule attachment during both meiotic divisions and that a complex known as the monopolin complex ensures that the protein kinase coorients...
In the fly antennal lobe projection neurons receive odor information from olfactory sensory neurons and transmit it to higher brain centers. However, projection neurons respond differently to odors than sensory neurons, despite the fact that they appear to have one-to-one connectivity. Shang et al. (2007) now describe the existence of excitatory neurons within the antennal lobe that may account for...
The etiology of cardiomyopathy in pregnant women remains unclear. In this issue, Hilfiker-Kleiner et al. (2007) report that a reduction in STAT3 and a concomitant increase in cathepsin D may be a cause of this disease. Cathepsin D generates an antiangiogenic cleavage product of the hormone prolactin. The authors show that an inhibitor of prolactin secretion may be useful in treating this disease.
Cell motility proceeds by cycles of edge protrusion, adhesion, and retraction. Whether these functions are coordinated by biochemical or biomechanical processes is unknown. We find that myosin II pulls the rear of the lamellipodial actin network, causing upward bending, edge retraction, and initiation of new adhesion sites. The network then separates from the edge and condenses over the myosin. Protrusion...
Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology and exposes women to high risk of mortality after delivery. Here, we show that female mice with a cardiomyocyte-specific deletion of stat3 develop PPCM. In these mice, cardiac cathepsin D (CD) expression and activity is enhanced and associated with the generation of a cleaved antiangiogenic and proapoptotic 16 kDa form of the nursing...
To illuminate the evolutionary pressure acting on the folding free energy landscapes of naturally occurring proteins, we have systematically characterized the folding free energy landscape of Top7, a computationally designed protein lacking an evolutionary history. Stopped-flow kinetics, circular dichroism, and NMR experiments reveal that there are at least three distinct phases in the folding of...
In this issue, Garcia-Bassets et al. (2007) show that spurious transcriptional activation by unliganded nuclear receptors is inhibited by histone lysine methylation. This inhibitory histone modification code is efficiently countered by the ligand-dependent recruitment of histone lysine demethylases, including lysine-specific demethylase 1 (LSD1), which appear to be used for this purpose by a number...
Genetics and pharmacology can elicit surprisingly different phenotypes despite targeting the same protein. This Essay explores these unexpected differences and their implications for biology and medicine.
Proteins of the death domain (DD) superfamily mediate assembly of oligomeric signaling complexes for the activation of caspases and kinases via unknown mechanisms. Here we report the crystal structure of the PIDD DD and RAIDD DD complex, which forms the core of the caspase-2-activating complex PIDDosome. Although RAIDD DD and PIDD DD are monomers, they assemble into a complex that comprises seven...
Nuclear receptors undergo ligand-dependent conformational changes that are required for corepressor-coactivator exchange, but whether there is an actual requirement for specific epigenetic landmarks to impose ligand dependency for gene activation remains unknown. Here we report an unexpected and general strategy that is based on the requirement for specific cohorts of inhibitory histone methyltransferases...
Cyclin-dependent kinase activation can prevent yeast cells from responding to mating pheromone. Strickfaden et al. (2007) now show that this block arises from the multisite phosphorylation of Ste5. This provides a beautiful example of how phosphorylation can produce decisive changes in protein function through bulk electrostatics, without the necessity of intricate conformational changes.
C. elegans worms hatching in the absence of food show growth arrest during the first larval stage (L1). While much has been learned about the later diapause, dauer, which worms enter under adverse conditions, much less is known about the mechanisms governing L1 arrest. Here we show that worms lacking activity of the asna-1 gene arrest growth reversibly at the L1 stage even when food is abundant. asna-1...
Most epithelial tissues self-renew throughout adult life due to the presence of multipotent stem cells and/or unipotent progenitor cells. Epithelial stem cells are specified during development and are controlled by epithelial-mesenchymal interactions. Despite morphological and functional differences among epithelia, common signaling pathways appear to control epithelial stem cell maintenance, activation,...
Yeast cells arrest in the G1 phase of the cell cycle upon exposure to mating pheromones. As cells commit to a new cycle, G1 CDK activity (Cln/CDK) inhibits signaling through the mating MAPK cascade. Here we show that the target of this inhibition is Ste5, the MAPK cascade scaffold protein. Cln/CDK disrupts Ste5 membrane localization by phosphorylating a cluster of sites that flank a small, basic,...
The generation of asymmetry is a key event in many developmental processes, including cell differentiation, embryonic axis specification, and organogenesis. Recent research highlights the identification of factors needed to establish stomata during plant development and the role that timing plays in directing left-right asymmetry during nervous system development in zebrafish. Other recent studies...
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