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39 Publications

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    03/07/02 | Neurobiology: a cool ion channel.
    Zuker CS
    Nature. 2002 Mar 7;416(6876):27-8. doi: 10.1038/416027a
    03/06/02 | Differences in nuclear gene expression between cells containing monomer and dimer mitochondrial genomes.
    Clark KM, Brown TA, Davidson MM, Papadopoulou LC, Clayton DA
    Gene. 2002 Mar 6;286(1):91-104

    It is known that point mutations and rearrangements (deletions and duplications) of mammalian mitochondrial DNA (mtDNA) can result in mitochondrial dysfunction and human disease. Very little attention has been paid to mtDNA circular dimers (a complex form consisting of two genomes joined head-to-tail) despite their close association with human neoplasia. MtDNA dimers are frequently found in human leukemia, but the clinical relevance of their presence remains unknown. To begin to investigate the role of circular dimer mtDNA in the tumorigenic phenotype, we have created isogenic cell lines containing monomer and dimer mitochondrial genomes and compared the respective nuclear mRNA expression using Affymetrix gene array analysis. Surprisingly, a large number of nuclear gene changes were observed, with one of the largest category of genes being associated with remodeling of the cell surface and extracellular matrix. Since cell growth, migration, apoptosis, and many other cellular processes are influenced by signals initiating from the cell surface, the changes associated with the presence of mtDNA dimers could lead to significant alterations in tumorigenic potential and/or progression.

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    Magee Lab
    03/01/02 | Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia.
    Abdulkadir SA, Magee JA, Peters TJ, Kaleem Z, Naughton CK, Humphrey PA, Milbrandt J
    Molecular and Cellular Biology. 2002 Mar;22(5):1495-503. doi: 10.1002/cbic.201000254

    The homeodomain-containing transcription factor NKX3.1 is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner. Loss of NKX3.1 protein expression is common in human prostate carcinomas and prostatic intraepithelial neoplasia (PIN) lesions and correlates with tumor progression. Disruption of the murine Nkx3.1 gene results in defects in prostate branching morphogenesis, secretions, and growth. To more closely mimic the pattern of NKX3.1 loss that occurs in human prostate tumors, we have used Cre- and loxP-mediated recombination to delete the Nkx3.1 gene in the prostates of adult transgenic mice. Conditional deletion of one or both alleles of Nkx3.1 leads to the development of preinvasive lesions that resemble PIN. The pattern of expression of several biomarkers (Ki-67, E-cadherin, and high-molecular-weight cytokeratins) in these PIN lesions resembled that observed in human cases of PIN. Furthermore, PIN foci in mice with conditional deletion of a single Nkx3.1 allele lose expression of the wild-type allele. Our results support the role of NKX3.1 as a prostate tumor suppressor and indicate a role for this gene in tumor initiation.

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    Egnor Lab
    03/01/02 | Detection of large interaural delays and its implication for models of binaural interaction.
    Saberi K, Takahashi Y, Egnor R, Farahbod H, Mazer J, Konishi M
    Journal of the Association for Research in Otolaryngology: JARO. 2002 Mar;3(1):80-8

    The interaural time difference (ITD) is a major cue to sound localization along the horizontal plane. The maximum natural ITD occurs when a sound source is positioned opposite to one ear. We examined the ability of owls and humans to detect large ITDs in sounds presented through headphones. Stimuli consisted of either broad or narrow bands of Gaussian noise, 100 ms in duration. Using headphones allowed presentation of ITDs that are greater than the maximum natural ITD. Owls were able to discriminate a sound leading to the left ear from one leading to the right ear, for ITDs that are 5 times the maximum natural delay. Neural recordings from optic-tectum neurons, however, show that best ITDs are usually well within the natural range and are never as large as ITDs that are behaviorally discriminable. A model of binaural crosscorrelation with short delay lines is shown to explain behavioral detection of large ITDs. The model uses curved trajectories of a cross-correlation pattern as the basis for detection. These trajectories represent side peaks of neural ITD-tuning curves and successfully predict localization reversals by both owls and human subjects.

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    03/01/02 | Nuclear degradation of p53 occurs during down-regulation of the p53 response after DNA damage.
    Shirangi TR, Zaika A, Moll UM
    The FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2002 Mar;16:420-2. doi: 10.1096/fj.01-0617fje

    The principal regulator of p53 stability is HDM2, an E3 ligase that mediates p53 degradation via the ubiquitin-26S proteasome pathway. The current model holds that p53 degradation occurs exclusively on cytoplasmic proteasomes and hence has an absolute requirement for nuclear export of p53 via the CRM-1 pathway. However, proteasomes are abundant in both cytosol and nucleus, and no studies have been done to determine under what physiological circumstances p53 degradation might occur in the nucleus. We analyzed HDM2-mediated degradation of endogenous p53 in the presence of various nuclear export inhibitors of CRM-1, including leptomycin B (LMB), a noncompetitive, specific, and fast-acting inhibitor; and HTLV1-Rex protein, a potent competitive inhibitor. We found that significant HDM2-mediated p53 degradation took place in the presence of LMB or HTLV1-Rex, indicating that endogenous p53 degradation occurs locally in the nucleus, in parallel to cytoplasmic degradation. Moreover, p53 null cells that coexpressed export-defective mutants of p53 and HDM2 retained partial competence for p53 degradation. It is important that nuclear degradation of p53 occurred during the poststress recovery phase of a p53 response, after DNA damage ceased. We propose that the capability of local p53 degradation within the nucleus provides a tighter and faster control during the down-regulatory phase, when an active p53 program needs to be turned off quickly.

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    02/14/02 | Drosophila Dscam is required for divergent segregation of sister branches and suppresses ectopic bifurcation of axons.
    Wang J, Zugates CT, Liang IH, Lee CJ, Lee T
    Neuron. 2002 Feb 14;33(4):559-71

    Axon bifurcation results in the formation of sister branches, and divergent segregation of the sister branches is essential for efficient innervation of multiple targets. From a genetic mosaic screen, we find that a lethal mutation in the Drosophila Down syndrome cell adhesion molecule (Dscam) specifically perturbs segregation of axonal branches in the mushroom bodies. Single axon analysis further reveals that Dscam mutant axons generate additional branches, which randomly segregate among the available targets. Moreover, when only one target remains, branching is suppressed in wild-type axons while Dscam mutant axons still form multiple branches at the original bifurcation point. Taken together, we conclude that Dscam controls axon branching and guidance such that a neuron can innervate multiple targets with minimal branching.

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    Tjian Lab
    02/08/02 | Structure, function, and activator-induced conformations of the CRSP coactivator.
    Taatjes DJ, Näär AM, Andel F, Nogales E, Tjian R
    Science. 2002 Feb 8;295(5557):1058-62. doi: 10.1073/pnas.1100640108

    The human cofactor complexes ARC (activator-recruited cofactor) and CRSP (cofactor required for Sp1 activation) mediate activator-dependent transcription in vitro. Although these complexes share several common subunits, their structural and functional relationships remain unknown. Here, we report that affinity-purified ARC consists of two distinct multisubunit complexes: a larger complex, denoted ARC-L, and a smaller coactivator, CRSP. Reconstituted in vitro transcription with biochemically separated ARC-L and CRSP reveals differential cofactor functions. The ARC-L complex is transcriptionally inactive, whereas the CRSP complex is highly active. Structural determination by electron microscopy (EM) and three-dimensional reconstruction indicate substantial differences in size and shape between ARC-L and CRSP. Moreover, EM analysis of independently derived CRSP complexes reveals distinct conformations induced by different activators. These results suggest that CRSP may potentiate transcription via specific activator-induced conformational changes.

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    02/01/02 | Rough eye is a gain-of-function allele of amos that disrupts regulation of the proneural gene atonal during Drosophila retinal differentiation.
    Chanut F, Woo K, Pereira S, Donohoe TJ, Chang S, Laverty TR, Jarman AP, Heberlein U
    Genetics. 2002 Feb;160(2):623-35

    The regular organization of the ommatidial lattice in the Drosophila eye originates in the precise regulation of the proneural gene atonal (ato), which is responsible for the specification of the ommatidial founder cells R8. Here we show that Rough eye (Roi), a dominant mutation manifested by severe roughening of the adult eye surface, causes defects in ommatidial assembly and ommatidial spacing. The ommatidial spacing defect can be ascribed to the irregular distribution of R8 cells caused by a disruption of the patterning of ato expression. Disruptions in the recruitment of other photoreceptors and excess Hedgehog production in differentiating cells may further contribute to the defects in ommatidial assembly. Our molecular characterization of the Roi locus demonstrates that it is a gain-of-function mutation of the bHLH gene amos that results from a chromosomal inversion. We show that Roi can rescue the retinal developmental defect of ato1 mutants and speculate that amos substitutes for some of ato's function in the eye or activates a residual function of the ato1 allele.

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    Baker Lab
    01/01/02 | A genomic analysis of gene expresson during the Drosophila life cycle.
    Baker B, Arbeitman M, Furlong E, Imam F, Johnson E, Null B
    Science. 2002:2270-75