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92 Publications

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    03/09/06 | Structural insight into gene transcriptional regulation and effector binding by the Lrp/AsnC family.
    Thaw P, Sedelnikova SE, Muranova T, Wiese S, Ayora S, Alonso JC, Brinkman AB, Akerboom J, van der Oost J, Rafferty JB
    Nucleic Acids Research. 2006 Mar 9;34(5):1439-49. doi: 10.1093/nar/gkl009

    The Lrp/AsnC family of transcriptional regulatory proteins is found in both archaea and bacteria. Members of the family influence cellular metabolism in both a global (Lrp) and specific (AsnC) manner, often in response to exogenous amino acid effectors. In the present study we have determined both the first bacterial and the highest resolution structures for members of the family. Escherichia coli AsnC is a specific gene regulator whose activity is triggered by asparagine binding. Bacillus subtilis LrpC is a global regulator involved in chromosome condensation. Our AsnC-asparagine structure is the first for a regulator-effector complex and is revealed as an octameric disc. Key ligand recognition residues are identified together with a route for ligand access. The LrpC structure reveals a stable octamer supportive of a topological role in dynamic DNA packaging. The structures yield significant clues to the functionality of Lrp/AsnC-type regulators with respect to ligand binding and oligomerization states as well as to their role in specific and global DNA regulation.

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    03/02/06 | Making the grade with models of persistent activity.
    Dudman JT, Siegelbaum SA
    Neuron. 2006 Mar 2;49(5):649-51. doi: 10.3389/fnana.2010.00147

    Persistent neural activity that outlasts an initial stimulus is thought to provide a mechanism for the transient storage of memory. In this issue of Neuron, Fransén et al. identify important principles for a cell-autonomous mechanism of graded persistent firing using an elegant combination of experimental and computational approaches.

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    Magee Lab
    03/01/06 | A systematic model to predict transcriptional regulatory mechanisms based on overrepresentation of transcription factor binding profiles.
    Chang L, Nagarajan R, Magee JA, Milbrandt J, Stormo GD
    Genome Research. 2006 Mar;16(3):405-13. doi: 10.1002/cbic.201000254

    An important aspect of understanding a biological pathway is to delineate the transcriptional regulatory mechanisms of the genes involved. Two important tasks are often encountered when studying transcription regulation, i.e., (1) the identification of common transcriptional regulators of a set of coexpressed genes; (2) the identification of genes that are regulated by one or several transcription factors. In this study, a systematic and statistical approach was taken to accomplish these tasks by establishing an integrated model considering all of the promoters and characterized transcription factors (TFs) in the genome. A promoter analysis pipeline (PAP) was developed to implement this approach. PAP was tested using coregulated gene clusters collected from the literature. In most test cases, PAP identified the transcription regulators of the input genes accurately. When compared with chromatin immunoprecipitation experiment data, PAP’s predictions are consistent with the experimental observations. When PAP was used to analyze one published expression-profiling data set and two novel coregulated gene sets, PAP was able to generate biologically meaningful hypotheses. Therefore, by taking a systematic approach of considering all promoters and characterized TFs in our model, we were able to make more reliable predictions about the regulation of gene expression in mammalian organisms.

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    03/01/06 | An in vitro fluorescence screen to identify antivirals that disrupt hepatitis B virus capsid assembly.
    Stray SJ, Johnson JM, Kopek BG, Zlotnick A
    Nature Biotechnology. 2006 Mar;24(3):358-62. doi: 10.1038/nbt1187

    Virus assembly has not been routinely targeted in the development of antiviral drugs, in part because of the lack of tractable methods for screening in vitro. We have developed an in vitro assay of hepatitis B virus (HBV) capsid assembly, based on fluorescence quenching of dye-labeled capsid protein, for testing potential inhibitors. This assay is adaptable to high-throughput screening and can identify small-molecule inhibitors of virus assembly that prevent, inappropriately accelerate and/or misdirect capsid formation to yield aberrant particles. An in vitro primary screen has the advantage of identifying promising lead compounds affecting assembly without the requirement that they be taken up by cells in culture and be nontoxic. Our approach may facilitate the identification of antivirals targeting viruses other than HBV, such as avian influenza and HIV.

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    03/01/06 | Bispecific antibodies for dual-modality cancer therapy: killing two signaling cascades with one stone.
    Marvin JS, Zhu Z
    Current Opinion in Drug Discovery & Development. 2006 Mar;9(2):184-93

    The additive and synergistic therapeutic effects derived from combinations of chemotherapeutic drugs and radiation have established an indispensable paradigm: cancer must be attacked on multiple fronts. However, the increased antitumor efficacy of such combinational regimens is also associated with severe systemic toxicity, as these drugs cannot selectively target tumor cells. Monoclonal antibodies (mAbs), which have exquisite specificity for their antigens, are becoming an increasingly important class of antitumor agents, as they enhance the efficacy of various therapeutic regimens without significantly increasing systemic toxicity. Furthermore, preclinical and early clinical evidence indicate that combinations of antibody-based drugs provide even greater efficacy with minimal side effects. Unfortunately, the research, manufacturing and regulatory costs of mAb development pose a significant barrier to the use of antibody-based combination therapies. An emerging alternative is the use of dual-targeting bispecific antibodies (BsAbs). BsAbs are derived from the recombination of variable domains of two antibodies with different specificities; BsAbs are thus capable of binding both antigens of their parental antibodies. With the recent progress that has been made in antibody engineering technology, BsAbs that simultaneously target two tumor-associated molecules (eg, growth factor receptors) are being heralded for their potential to deliver two therapeutic moieties in a single molecule.

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    Tjian Lab
    03/01/06 | Cryo-electron microscopy studies of human TFIID: conformational breathing in the integration of gene regulatory cues.
    Grob P, Cruse MJ, Inouye C, Peris M, Penczek PA, Tjian R, Nogales E
    Structure. 2006 Mar;14(3):511-20. doi: 10.1073/pnas.1100640108

    The multisubunit transcription factor TFIID is essential for directing eukaryotic promoter recognition and mediating interactions with activators/cofactors during assembly of the preinitiation complex. Despite its central role in transcription initiation and regulation, structural knowledge of the TFIID complex has so far been largely limited to electron microscopy studies of negatively stained samples. Here, we present a cryo-electron microscopy 3D reconstruction of the large endogenous human TFIID complex. The improved cryopreservation has allowed for a more detailed definition of the structural elements in the complex and for the detection, by an extensive statistical analysis of the data, of a conformational opening and closing of the cavity central to the TFIID architecture. We propose that these density rearrangements in the structure are a likely reflection of the plasticity of the interactions between TFIID and its many partner proteins.

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    03/01/06 | High-speed pollen release in the white mulberry tree, Morus alba L.
    Taylor PE, Card GM, House J, Dickinson MH, Flagan RC
    Sexual Plant Reproduction. 2006 Mar;19(1):19-24. doi: 10.1007/s00497-005-0018-9

    Anemophilous plants described as catapulting pollen explosively into the air have rarely attracted detailed examination. We investigated floral anthesis in a male mulberry tree with high-speed video and a force probe. The stamen was inflexed within the floral bud. Exposure to dry air initially resulted in a gradual movement of the stamen. This caused fine threads to tear at the stomium, ensuring dehiscence of the anther, and subsequently enabled the anther to slip off a restraining pistillode. The sudden release of stored elastic energy in the spring-like filament drove the stamen to straighten in less than 25 μs, and reflex the petals to velocities in excess of half the speed of sound. This is the fastest motion yet observed in biology, and approaches the theoretical physical limits for movements in plants.

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    Tjian Lab
    03/01/06 | Nutrient availability and growth: regulation of insulin signaling by dFOXO/FOXO1.
    Puig O, Tjian R
    Cell Cycle. 2006 Mar;5(5):503-5. doi: 10.1073/pnas.1100640108

    Organisms adjust their rate of growth depending on the availability of nutrients. Thus, when environmental conditions limit nutrients, growth is slowed and is only restored after food again becomes abundant. Many aspects of the molecular mechanisms that govern this complex control system remain unknown. However, it has been shown that the insulin/IGF-1 (insulin-like growth factor 1) receptor pathway, together with the FOXO family of transcription factors, play an important role in this process. Recent studies with the fruit fly Drosophila melanogaster have provided new insights into the regulatory circuitry that controls both growth and gene expression in response to nutrient availability.

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    Tjian Lab
    02/21/06 | Cell-type-selective induction of c-jun by TAF4b directs ovarian-specific transcription networks.
    Geles KG, Freiman RN, Liu W, Zheng S, Voronina E, Tjian R
    Proceedings of the National Academy of Sciences of the United States of America. 2006 Feb 21;103(8):2594-9. doi: 10.1073/pnas.1100640108

    Cell-type-selective expression of the TFIID subunit TAF(II)105 (renamed TAF4b) in the ovary is essential for proper follicle development. Although a multitude of signaling pathways required for folliculogenesis have been identified, downstream transcriptional integrators of these signals remain largely unknown. Here, we show that TAF4b controls the granulosa-cell-specific expression of the proto-oncogene c-jun, and together they regulate transcription of ovary-selective promoters. Instead of using cell-type-specific activators, our findings suggest that the coactivator TAF4b regulates the expression of tissue-specific genes, at least in part, through the cell-type-specific induction of c-jun, a ubiquitous activator. Importantly, the loss of TAF4b in ovarian granulosa cells disrupts cellular morphologies and interactions during follicle growth that likely contribute to the infertility observed in TAF4b-null female mice. These data highlight a mechanism for potentiating tissue-selective functions of the basal transcription machinery and reveal intricate networks of gene expression that orchestrate ovarian-specific functions and cell morphology.

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    Magee Lab
    02/15/06 | State-dependent dendritic computation in hippocampal CA1 pyramidal neurons.
    Gasparini S, Magee JC
    The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2006 Feb 15;26(7):2088-100. doi: 10.1002/cbic.201000254

    Depending on the behavioral state, hippocampal CA1 pyramidal neurons receive very distinct patterns of synaptic input and likewise produce very different output patterns. We have used simultaneous dendritic and somatic recordings and multisite glutamate uncaging to investigate the relationship between synaptic input pattern, the form of dendritic integration, and action potential output in CA1 neurons. We found that when synaptic input arrives asynchronously or highly distributed in space, the dendritic arbor performs a linear integration that allows the action potential rate and timing to vary as a function of the quantity of the input. In contrast, when synaptic input arrives synchronously and spatially clustered, the dendritic compartment receiving the clustered input produces a highly nonlinear integration that leads to an action potential output that is extraordinarily precise and invariant. We also present evidence that both of these forms of information processing may be independently engaged during the two distinct behavioral states of the hippocampus such that individual CA1 pyramidal neurons could perform two different state-dependent computations: input strength encoding during theta states and feature detection during sharp waves.

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