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6 Publications

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    Tjian Lab
    08/15/03 | Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway.
    Puig O, Marr MT, Ruhf ML, Tjian R
    Genes & Development. 2003 Aug 15;17(16):2006-20. doi: 10.1073/pnas.1100640108

    The Drosophila insulin receptor (dInR) regulates cell growth and proliferation through the dPI3K/dAkt pathway, which is conserved in metazoan organisms. Here we report the identification and functional characterization of the Drosophila forkhead-related transcription factor dFOXO, a key component of the insulin signaling cascade. dFOXO is phosphorylated by dAkt upon insulin treatment, leading to cytoplasmic retention and inhibition of its transcriptional activity. Mutant dFOXO lacking dAkt phosphorylation sites no longer responds to insulin inhibition, remains in the nucleus, and is constitutively active. dFOXO activation in S2 cells induces growth arrest and activates two key players of the dInR/dPI3K/dAkt pathway: the translational regulator d4EBP and the dInR itself. Induction of d4EBP likely leads to growth inhibition by dFOXO, whereas activation of dInR provides a novel transcriptionally induced feedback control mechanism. Targeted expression of dFOXO in fly tissues regulates organ size by specifying cell number with no effect on cell size. Our results establish dFOXO as a key transcriptional regulator of the insulin pathway that modulates growth and proliferation.

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    Tjian Lab
    07/10/03 | Transcription regulation and animal diversity.
    Levine M, Tjian R
    Nature. 2003 Jul 10;424:147-51. doi: 10.1073/pnas.1100640108

    Whole-genome sequence assemblies are now available for seven different animals, including nematode worms, mice and humans. Comparative genome analyses reveal a surprising constancy in genetic content: vertebrate genomes have only about twice the number of genes that invertebrate genomes have, and the increase is primarily due to the duplication of existing genes rather than the invention of new ones. How, then, has evolutionary diversity arisen? Emerging evidence suggests that organismal complexity arises from progressively more elaborate regulation of gene expression.

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    Tjian Lab
    06/01/03 | Diversified transcription initiation complexes expand promoter selectivity and tissue-specific gene expression.
    Hochheimer A, Tjian R
    Genes & Development. 2003 Jun 1;17(11):1309-20. doi: 10.1073/pnas.1100640108
    Tjian Lab
    06/01/03 | Targeting genes and transcription factors to segregated nuclear compartments.
    Isogai Y, Tjian R
    Current Opinion in Cell Biology. 2003 Jun;15(3):296-303. doi: 10.1073/pnas.1100640108

    With increasingly detailed images of nuclear structures revealed by advanced microscopy, a remarkably compartmentalized cell nucleus has come into focus. Although this complex nuclear organization remains largely unexplored, some progress has been made in deciphering the functional aspects of various subnuclear structures, revealing how this elaborate framework can influence gene activation. Several recent studies have helped illustrate how cells might utilize the nuclear architecture as an additional level of transcriptional control, perhaps by targeting genes and regulatory factors to specific sites within the nucleus that are designated for active RNA synthesis.

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    Tjian Lab
    02/01/03 | Bromodomains mediate an acetyl-histone encoded antisilencing function at heterochromatin boundaries.
    Ladurner AG, Inouye C, Jain R, Tjian R
    Molecular Cell. 2003 Feb;11(2):365-76. doi: 10.1073/pnas.1100640108

    Bromodomains bind acetylated histone H4 peptides in vitro. Since many chromatin remodeling complexes and the general transcription factor TFIID contain bromodomains, they may link histone acetylation to increased transcription. Here we show that yeast Bdf1 bromodomains recognize endogenous acetyl-histone H3/H4 as a mechanism for chromatin association in vivo. Surprisingly, deletion of BDF1 or a Bdf1 mutation that abolishes histone binding leads to transcriptional downregulation of genes located at heterochromatin-euchromatin boundaries. Wild-type Bdf1 protein imposes a physical barrier to the spreading of telomere- and mating-locus-proximal SIR proteins. Biochemical experiments indicate that Bdf1 competes with the Sir2 deacetylase for binding to acetylated histone H4. These data suggest an active role for Bdf1 in euchromatin maintenance and antisilencing through a histone tail-encoded boundary function.

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    Tjian Lab
    01/10/03 | Regulating the regulators: lysine modifications make their mark.
    Freiman RN, Tjian R
    Cell. 2003 Jan 10;112(1):11-7. doi: 10.1073/pnas.1100640108

    Decades of research have uncovered much of the molecular machinery responsible for establishing and maintaining proper gene transcription patterns in eukaryotes. Although the composition of this machinery is largely known, mechanisms regulating its activity by covalent modification are just coming into focus. Here, we review several cases of ubiquitination, sumoylation, and acetylation that link specific covalent modification of the transcriptional apparatus to their regulatory function. We propose that potential cascades of modifications serve as molecular rheostats that fine-tune the control of transcription in diverse organisms.

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