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Critical Role of Amyloid-like Oligomers of Drosophila Orb2 in the Persistence of Memory.
Publication Date: 2012 Jan 24 PMID: 22284910
Authors: Majumdar, A. - Cesario, W. C. - White-Grindley, E. - Jiang, H. - Ren, F. - Khan, M. R. - Li, L. - Choi, E. M. - Kannan, K. - Guo, F. - Unruh, J. - Slaughter, B. - Si, K.
Journal: Cell
A long-standing question in the study of long-term memory is how a memory trace persists for years when the proteins that initiated the process turn over and disappear within days. Previously, we postulated that self-sustaining amyloidogenic oligomers of cytoplasmic polyadenylation element-binding protein (CPEB) provide a mechanism for the maintenance of activity-dependent synaptic changes and, thus, the persistence of memory. Here, we found that the Drosophila CPEB Orb2 forms amyloid-like oligomers, and oligomers are enriched in the synaptic membrane fraction. Of the two protein isoforms of Orb2, the amyloid-like oligomer formation is dependent on the Orb2A form. A point mutation in the prion-like domain of Orb2A, which reduced amyloid-like oligomerization of Orb2, did not interfere with learning or memory persisting up to 24 hr. However the mutant flies failed to stabilize memory beyond 48 hr. These results support the idea that amyloid-like oligomers of neuronal CPEB are critical for the persistence of long-term memory.
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Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome.
Publication Date: 2012 Jan 18 PMID: 22265598
Authors: Sexton, T. - Yaffe, E. - Kenigsberg, E. - Bantignies, F. - Leblanc, B. - Hoichman, M. - Parrinello, H. - Tanay, A. - Cavalli, G.
Journal: Cell
Chromosomes are the physical realization of genetic information and thus form the basis for its readout and propagation. Here we present a high-resolution chromosomal contact map derived from a modified genome-wide chromosome conformation capture approach applied to Drosophila embryonic nuclei. The data show that the entire genome is linearly partitioned into well-demarcated physical domains that overlap extensively with active and repressive epigenetic marks. Chromosomal contacts are hierarchically organized between domains. Global modeling of contact density and clustering of domains show that inactive domains are condensed and confined to their chromosomal territories, whereas active domains reach out of the territory to form remote intra- and interchromosomal contacts. Moreover, we systematically identify specific long-range intrachromosomal contacts between Polycomb-repressed domains. Together, these observations allow for quantitative prediction of the Drosophila chromosomal contact map, laying the foundation for detailed studies of chromosome structure and function in a genetically tractable system.
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SnapShot: Bioactive Lysophospholipids.
Publication Date: 2012 Jan 20 PMID: 22265422
Authors: Moolenaar, W. H. - Hla, T.
Journal: Cell
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Computational modeling of pancreatic cancer reveals kinetics of metastasis suggesting optimum treatment strategies.
Publication Date: 2012 Jan 20 PMID: 22265421
Authors: Haeno, H. - Gonen, M. - Davis, M. B. - Herman, J. M. - Iacobuzio-Donahue, C. A. - Michor, F.
Journal: Cell
Pancreatic cancer is a leading cause of cancer-related death, largely due to metastatic dissemination. We investigated pancreatic cancer progression by utilizing a mathematical framework of metastasis formation together with comprehensive data of 228 patients, 101 of whom had autopsies. We found that pancreatic cancer growth is initially exponential. After estimating the rates of pancreatic cancer growth and dissemination, we determined that patients likely harbor metastases at diagnosis and predicted the number and size distribution of metastases as well as patient survival. These findings were validated in an independent database. Finally, we analyzed the effects of different treatment modalities, finding that therapies that efficiently reduce the growth rate of cells earlier in the course of treatment appear to be superior to upfront tumor resection. These predictions can be validated in the clinic. Our interdisciplinary approach provides insights into the dynamics of pancreatic cancer metastasis and identifies optimum therapeutic interventions.
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EMT and Dissemination Precede Pancreatic Tumor Formation.
Publication Date: 2012 Jan 20 PMID: 22265420
Authors: Rhim, A. D. - Mirek, E. T. - Aiello, N. M. - Maitra, A. - Bailey, J. M. - McAllister, F. - Reichert, M. - Beatty, G. L. - Rustgi, A. K. - Vonderheide, R. H. - Leach, S. D. - Stanger, B. Z.
Journal: Cell
Metastasis is the leading cause of cancer-associated death but has been difficult to study because it involves a series of rare, stochastic events. To capture these events, we developed a sensitive method to tag and track pancreatic epithelial cells in a mouse model of pancreatic cancer. Tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-to-mesenchymal transition (EMT). Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.
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HSF-1 Regulators DDL-1/2 Link Insulin-like Signaling to Heat-Shock Responses and Modulation of Longevity.
Publication Date: 2012 Jan 20 PMID: 22265419
Authors: Chiang, W. C. - Ching, T. T. - Lee, H. C. - Mousigian, C. - Hsu, A. L.
Journal: Cell
Extended longevity is often correlated with increased resistance against various stressors. Insulin/IGF-1-like signaling (IIS) is known to have a conserved role in aging and cellular mechanisms against stress. In C. elegans, genetic studies suggest that heat-shock transcription factor HSF-1 is required for IIS to modulate longevity. Here, we report that the activity of HSF-1 is regulated by IIS. This regulation occurs at an early step of HSF-1 activation via two HSF-1 regulators, DDL-1 and DDL-2. Inhibition of DDL-1/2 increases longevity and thermotolerance in an hsf-1-dependent manner. Furthermore, biochemical analyses suggest that DDL-1/2 negatively regulate HSF-1 activity by forming a protein complex with HSF-1. The formation of this complex (DHIC) is affected by the phosphorylation status of DDL-1. Both the formation of DHIC and the phosphorylation of DDL-1 are controlled by IIS. Our findings point to DDL-1/2 as a link between IIS and the HSF-1 pathway.
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Local zones of endoplasmic reticulum complexity confine cargo in neuronal dendrites.
Publication Date: 2012 Jan 20 PMID: 22265418
Authors: Cui-Wang, T. - Hanus, C. - Cui, T. - Helton, T. - Bourne, J. - Watson, D. - Harris, K. M. - Ehlers, M. D.
Journal: Cell
Following synthesis, integral membrane proteins dwell in the endoplasmic reticulum (ER) for variable periods that are typically rate limiting for plasma membrane delivery. In neurons, the ER extends for hundreds of microns as an anastomosing network throughout highly branched dendrites. However, little is known about the mobility, spatial scales, or dynamic regulation of cargo in the dendritic ER. Here, we show that membrane proteins, including AMPA-type glutamate receptors, rapidly diffuse within the continuous network of dendritic ER but are confined by increased ER complexity at dendritic branch points and near dendritic spines. The spatial range of receptor mobility is rapidly restricted by type I mGluR signaling through a mechanism involving protein kinase C (PKC) and the ER protein CLIMP63. Moreover, local zones of ER complexity compartmentalize ER export and correspond to sites of new dendritic branches. Thus, local control of ER complexity spatially scales secretory trafficking within elaborate dendritic arbors.
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Mutation of a U2 snRNA Gene Causes Global Disruption of Alternative Splicing and Neurodegeneration.
Publication Date: 2012 Jan 20 PMID: 22265417
Authors: Jia, Y. - Mu, J. C. - Ackerman, S. L.
Journal: Cell
Although uridine-rich small nuclear RNAs (U-snRNAs) are essential for pre-mRNA splicing, little is known regarding their function in the regulation of alternative splicing or of the biological consequences of their dysfunction in mammals. Here, we demonstrate that mutation of Rnu2-8, one of the mouse multicopy U2 snRNA genes, causes ataxia and neurodegeneration. Coincident with the observed pathology, the level of mutant U2 RNAs was highest in the cerebellum and increased after granule neuron maturation. Furthermore, neuron loss was strongly dependent on the dosage of mutant and wild-type snRNA genes. Comprehensive transcriptome analysis identified a group of alternative splicing events, including the splicing of small introns, which were disrupted in the mutant cerebellum. Our results suggest that the expression of mammalian U2 snRNA genes, previously presumed to be ubiquitous, is spatially and temporally regulated, and dysfunction of a single U2 snRNA causes neuron degeneration through distortion of pre-mRNA splicing.
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Gene regulatory logic for reading the sonic hedgehog signaling gradient in the vertebrate neural tube.
Publication Date: 2012 Jan 20 PMID: 22265416
Authors: Balaskas, N. - Ribeiro, A. - Panovska, J. - Dessaud, E. - Sasai, N. - Page, K. M. - Briscoe, J. - Ribes, V.
Journal: Cell
Secreted signals, known as morphogens, provide the positional information that organizes gene expression and cellular differentiation in many developing tissues. In the vertebrate neural tube, Sonic Hedgehog (Shh) acts as a morphogen to control the pattern of neuronal subtype specification. Using an in vivo reporter of Shh signaling, mouse genetics, and systems modeling, we show that a spatially and temporally changing gradient of Shh signaling is interpreted by the regulatory logic of a downstream transcriptional network. The design of the network, which links three transcription factors to Shh signaling, is responsible for differential spatial and temporal gene expression. In addition, the network renders cells insensitive to fluctuations in signaling and confers hysteresis-memory of the signal. Our findings reveal that morphogen interpretation is an emergent property of the architecture of a transcriptional network that provides robustness and reliability to tissue patterning.
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Mutant p53 Disrupts Mammary Tissue Architecture via the Mevalonate Pathway.
Publication Date: 2012 Jan 20 PMID: 22265415
Authors: Freed-Pastor, W. A. - Mizuno, H. - Zhao, X. - Langerod, A. - Moon, S. H. - Rodriguez-Barrueco, R. - Barsotti, A. - Chicas, A. - Li, W. - Polotskaia, A. - Bissell, M. J. - Osborne, T. F. - Tian, B. - Lowe, S. W. - Silva, J. M. - Borresen-Dale, A. L. - Levine, A. J. - Bargonetti, J. - Prives, C.
Journal: Cell
p53 is a frequent target for mutation in human tumors, and mutant p53 proteins can actively contribute to tumorigenesis. We employed a three-dimensional culture model in which nonmalignant breast epithelial cells form spheroids reminiscent of acinar structures found in vivo, whereas breast cancer cells display highly disorganized morphology. We found that mutant p53 depletion is sufficient to phenotypically revert breast cancer cells to a more acinar-like morphology. Genome-wide expression analysis identified the mevalonate pathway as significantly upregulated by mutant p53. Statins and sterol biosynthesis intermediates reveal that this pathway is both necessary and sufficient for the phenotypic effects of mutant p53 on breast tissue architecture. Mutant p53 associates with sterol gene promoters at least partly via SREBP transcription factors. Finally, p53 mutation correlates with highly expressed sterol biosynthesis genes in human breast tumors. These findings implicate the mevalonate pathway as a therapeutic target for tumors bearing mutations in p53.
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