SwePub
Sök i SwePub databas

  Utökad sökning

Träfflista för sökning "L773:0890 9369 "

Sökning: L773:0890 9369

  • Resultat 1-50 av 109
Sortera/gruppera träfflistan
   
NumreringReferensOmslagsbildHitta
1.
  • Aase, Karin, et al. (författare)
  • Angiomotin regulates endothelial cell migration during embryonic angiogenesis
  • 2007
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 21:16, s. 2055-2068
  • Tidskriftsartikel (refereegranskat)abstract
    • The development of the embryonic vascular system into a highly ordered network requires precise control over the migration and branching of endothelial cells (ECs). We have previously identified angiomotin (Amot) as a receptor for the angiogenesis inhibitor angiostatin. Furthermore, DNA vaccination targeting Amot inhibits angiogenesis and tumor growth. However, little is known regarding the role of Amot in physiological angiogenesis. We therefore investigated the role of Amot in embryonic neovascularization during zebrafish and mouse embryogenesis. Here we report that knockdown of Amot in zebrafish reduced the number of filopodia of endothelial tip cells and severely impaired the migration of intersegmental vessels. We further show that 75% of Amot knockout mice die between embryonic day 11 (E11) and E11.5 and exhibit severe vascular insufficiency in the intersomitic region as well as dilated vessels in the brain. Furthermore, using ECs differentiated from embryonic stem (ES) cells, we demonstrate that Amot-deficient cells have intact response to vascular endothelial growth factor (VEGF) in regard to differentiation and proliferation. However, the chemotactic response to VEGF was abolished in Amot-deficient cells. We provide evidence that Amot is important for endothelial polarization during migration and that Amot controls Rac1 activity in endothelial and epithelial cells. Our data demonstrate a critical role for Amot during vascular patterning and endothelial polarization.
  •  
2.
  • Abramsson, Alexandra, 1973, et al. (författare)
  • Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development
  • 2007
  • Ingår i: GENES & DEVELOPMENT. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 21:3, s. 316-331
  • Tidskriftsartikel (refereegranskat)abstract
    • During vascular development, endothelial platelet-derived growth factor B (PDGF-B) is critical for pericyte recruitment. Deletion of the conserved C-terminal heparin-binding motif impairs PDGF-BB retention and pericyte recruitment in vivo, suggesting a potential role for heparan sulfate (HS) in PDGF-BB function during vascular development. We studied the participation of HS chains in pericyte recruitment using two mouse models with altered HS biosynthesis. Reduction of N-sulfation due to deficiency in N-deacetylase/N-sulfotransferase-1 attenuated PDGF-BB binding in vitro, and led to pericyte detachment and delayed pericyte migration in vivo. Reduced N-sulfation also impaired PDGF-BB signaling and directed cell migration, but not proliferation. In contrast, HS from glucuronyl C5-epimerase mutants, which is extensively N- and 6-O-sulfated, but lacks 2-O-sulfated L-iduronic acid residues, retained PDGF-BB in vitro, and pericyte recruitment in vivo was only transiently delayed. These observations were supported by in vitro characterization of the structural features in HS important for PDGF-BB binding. We conclude that pericyte recruitment requires HS with sufficiently extended and appropriately spaced N-sulfated domains to retain PDGF-BB and activate PDGF receptor β (PDGFRβ) signaling, whereas the detailed sequence of monosaccharide and sulfate residues does not appear to be important for this interaction.
  •  
3.
  • AlzhanovaEricsson, AT, et al. (författare)
  • A protein of the SR family of splicing factors binds extensively to exonic Balbiani ring pre-mRNA and accompanies the RNA from the gene to the nuclear pore
  • 1996
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 10:22, s. 2881-2893
  • Tidskriftsartikel (refereegranskat)abstract
    • We report on the molecular cloning and intracellular localization of a heterogeneous nuclear ribonucleoprotein (hnRNP), Ct-hrp45, one of the major components of pre-mRNP particles in Chironomus tentans. It is shown that hrp45 belongs to the SR family of splicing factors and exhibits high sequence similarity to Drosophila SRp55/B52 and human SF2/ASF. The distribution of hrp45 within the C. tentans salivary gland cells is studied by immunocytology. The hrp45 protein is found to be abundant in the nucleus, whereas it is undetectable in the cytoplasm. The fate of hrp45 in specific pre-mRNP particles, the Balbiani ring (BR) granules, is revealed by immunoelectron microscopy. It is observed that hrp45 is associated with the growing BR pre-mRNP particles and is being added continuously concomitant with the growth of the transcript, indicating that hrp45 is bound extensively to exon 4, which comprises 80-90% of the primary transcript. Furthermore, hrp45 remains bound to the BR RNP particles in the nucleoplasm and is not released until the particles translocate through the nuclear pore. Thus, hrp45 behaves as an hnRNP protein linked to exon RNA (and perhaps also to the introns) rather than as a spliceosome component connected to the assembly and disassembly of spliceosomes. It seems that hrp45, and possibly also other SR family proteins, is playing an important role in the structural organization of pre-mRNP particles and is perhaps participating not only in splicing but also in other intranuclear events.
  •  
4.
  • Andrae, J, et al. (författare)
  • Role of platelet-derived growth factors in physiology and medicine
  • 2008
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 22:10, s. 1276-1312
  • Tidskriftsartikel (refereegranskat)abstract
    • Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have served as prototypes for growth factor and receptor tyrosine kinase function for more than 25 years. Studies of PDGFs and PDGFRs in animal development have revealed roles for PDGFR-α signaling in gastrulation and in the development of the cranial and cardiac neural crest, gonads, lung, intestine, skin, CNS, and skeleton. Similarly, roles for PDGFR-β signaling have been established in blood vessel formation and early hematopoiesis. PDGF signaling is implicated in a range of diseases. Autocrine activation of PDGF signaling pathways is involved in certain gliomas, sarcomas, and leukemias. Paracrine PDGF signaling is commonly observed in epithelial cancers, where it triggers stromal recruitment and may be involved in epithelial–mesenchymal transition, thereby affecting tumor growth, angiogenesis, invasion, and metastasis. PDGFs drive pathological mesenchymal responses in vascular disorders such as atherosclerosis, restenosis, pulmonary hypertension, and retinal diseases, as well as in fibrotic diseases, including pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulosclerosis, and cardiac fibrosis. We review basic aspects of the PDGF ligands and receptors, their developmental and pathological functions, principles of their pharmacological inhibition, and results using PDGF pathway-inhibitory or stimulatory drugs in preclinical and clinical contexts.
  •  
5.
  • Asayesh, Amir, et al. (författare)
  • Spleen versus pancreas : strict control of organ interrelationship revealed by analyses of Bapx1-/- mice.
  • 2006
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 20:16, s. 2208-2213
  • Tidskriftsartikel (refereegranskat)abstract
    • During early stages of pancreatic development, the mesenchyme that contributes to the spleen overlies the dorsal pancreatic endoderm. Here, we show that interactions between splenic mesenchyme and pancreas proceed via a highly orchestrated morphogenetic program. Disruption of morphogenesis, as occurs in the Bapx1(Nkx3.2)−/− embryo, results in transformation of these tissues into well-organized, ectopic gut-like structures. Bapx1 plays a crucial organizing role effecting position and separation of the spleen and pancreas to prevent this metaplastic transformation. Similar transformations occur in organ cultures employing wild-type pancreatic endoderm and spleen mesenchyme, revealing the developmental plasticity of the pancreas and that precise spatial and temporal control of tissue interactions are required for development of both organs.
  •  
6.
  • Barsoum, Emad, 1979-, et al. (författare)
  • {alpha}3, a transposable element that promotes host sexual reproduction
  • 2010
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 24:15, s. 33-44
  • Tidskriftsartikel (refereegranskat)abstract
    • Theoretical models predict that selfish DNA elements require host sex to persist in a population. Therefore, a transposon that induces sex would strongly favor its own spread. We demonstrate that a protein homologous to transposases, called alpha3, was essential for mating type switch in Kluyveromyces lactis. Mutational analysis showed that amino acids conserved among transposases were essential for its function. During switching, sequences in the 5' and 3' flanking regions of the alpha3 gene were joined, forming a DNA circle, showing that alpha3 mobilized from the genome. The sequences encompassing the alpha3 gene circle junctions in the mating type alpha (MATalpha) locus were essential for switching from MATalpha to MATa, suggesting that alpha3 mobilization was a coupled event. Switching also required a DNA-binding protein, Mating type switch 1 (Mts1), whose binding sites in MATalpha were important. Expression of Mts1 was repressed in MATa/MATalpha diploids and by nutrients, limiting switching to haploids in low-nutrient conditions. A hairpin-capped DNA double-strand break (DSB) was observed in the MATa locus in mre11 mutant strains, indicating that mating type switch was induced by MAT-specific DSBs. This study provides empirical evidence for selfish DNA promoting host sexual reproduction by mediating mating type switch.
  •  
7.
  • Batista, Rita, et al. (författare)
  • Auxin regulates endosperm cellularization in Arabidopsis
  • 2019
  • Ingår i: Genes and Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 33, s. 466-476
  • Tidskriftsartikel (refereegranskat)abstract
    • The endosperm is an ephemeral tissue that nourishes the developing embryo, similar to the placenta in mammals. In most angiosperms, endosperm development starts as a syncytium, in which nuclear divisions are not followed by cytokinesis. The timing of endosperm cellularization largely varies between species, and the event triggering this transition remains unknown. Here we show that increased auxin biosynthesis in the endosperm prevents its cellularization, leading to seed arrest. Auxin-overproducing seeds phenocopy paternal-excess triploid seeds derived from hybridizations of diploid maternal plants with tetraploid fathers. Concurrently, auxin-related genes are strongly overexpressed in triploid seeds, correlating with increased auxin activity. Reducing auxin biosynthesis and signaling reestablishes endosperm cellularization in triploid seeds and restores their viability, highlighting a causal role of increased auxin in preventing endosperm cellularization. We propose that auxin determines the time of endosperm cellularization, and thereby uncovered a central role of auxin in establishing hybridization barriers in plants.
  •  
8.
  • Bauren, G, et al. (författare)
  • Transcriptional termination in the Balbiani ring 1 gene is closely coupled to 3'-end formation and excision of the 3'-terminal intron
  • 1998
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 12:17, s. 2759-2769
  • Tidskriftsartikel (refereegranskat)abstract
    • We have analyzed transcription termination, 3′-end formation, and excision of the 3′-terminal intron in vivo in the Balbiani ring 1 (BR1) gene and its pre-mRNA. We show that full-length RNA transcripts are evenly spaced on the gene from a position 300 bp upstream to a region 500–700 bp downstream of the polyadenylation sequence. Very few full-length transcripts and no short, cleaved, nascent transcripts could be observed downstream of this region. Pre-mRNA with 10–20 adenylate residues accumulates at the active gene and then rapidly leaves from the gene locus. Only polyadenylated pre-mRNAs could be detected in the nucleoplasm. Our results are consistent with the hypothesis that transcription termination occurs in a narrow region for the majority of transcripts, simultaneous with 3′-end formation. Excision of the 3′-terminal intron occurs before 3′-end formation in about 5% of the nascent transcripts. When transcription terminates, 3′ cleavage takes place and 10–20 adenylate residues are added, the 3′-terminal intron is excised from additionally about 75% of the pre-mRNA at the gene locus. Our data support a close temporal and spatial coupling of transcription termination and the cleavage and initial polyadenylation of 3′-end formation. Excision of the 3′-terminal intron is highly stimulated as the cleavage/polyadenylation complex assembles and 3′-end formation is initiated.
  •  
9.
  • Bergink, S, et al. (författare)
  • DNA damage triggers nucleotide excision repair-dependent monoubiquitylation of histone H2A
  • 2006
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 20:10, s. 1343-1352
  • Tidskriftsartikel (refereegranskat)abstract
    • Chromatin changes within the context of DNA repair remain largely obscure. Here we show that DNA damage induces monoubiquitylation of histone H2A in the vicinity of DNA lesions. Ultraviolet (UV)-induced monoubiquitylation of H2A is dependent on functional nucleotide excision repair and occurs after incision of the damaged strand. The ubiquitin ligase Ring2 is required for the DNA damage-induced H2A ubiquitylation. UV-induced ubiquitylation of H2A is dependent on the DNA damage signaling kinase ATR (ATM- and Rad3-related) but not the related kinase ATM (ataxia telangiectasia-mutated). Although the response coincides with phosphorylation of variant histone H2AX, H2AX was not required for H2A ubiquitylation. Together our data show that monoubiquitylation of H2A forms part of the cellular response to UV damage and suggest a role of this modification in DNA repair-induced chromatin remodeling.
  •  
10.
  • Bergsland, M, et al. (författare)
  • Sequentially acting Sox transcription factors in neural lineage development
  • 2011
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 25:23, s. 2453-2464
  • Tidskriftsartikel (refereegranskat)abstract
    • Pluripotent embryonic stem (ES) cells can generate all cell types, but how cell lineages are initially specified and maintained during development remains largely unknown. Different classes of Sox transcription factors are expressed during neurogenesis and have been assigned important roles from early lineage specification to neuronal differentiation. Here we characterize the genome-wide binding for Sox2, Sox3, and Sox11, which have vital functions in ES cells, neural precursor cells (NPCs), and maturing neurons, respectively. The data demonstrate that Sox factor binding depends on developmental stage-specific constraints and reveal a remarkable sequential binding of Sox proteins to a common set of neural genes. Interestingly, in ES cells, Sox2 preselects for neural lineage-specific genes destined to be bound and activated by Sox3 in NPCs. In NPCs, Sox3 binds genes that are later bound and activated by Sox11 in differentiating neurons. Genes prebound by Sox proteins are associated with a bivalent chromatin signature, which is resolved into a permissive monovalent state upon binding of activating Sox factors. These data indicate that a single key transcription factor family acts sequentially to coordinate neural gene expression from the early lineage specification in pluripotent cells to later stages of neuronal development.
  •  
11.
  • Bergsland, M, et al. (författare)
  • The establishment of neuronal properties is controlled by Sox4 and Sox11
  • 2006
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 20:24, s. 3475-3486
  • Tidskriftsartikel (refereegranskat)abstract
    • The progression of neurogenesis relies on proneural basic helix–loop–helix (bHLH) transcription factors. These factors operate in undifferentiated neural stem cells and induce cell cycle exit and the initiation of a neurogenic program. However, the transient expression of proneural bHLH proteins in neural progenitors indicates that expression of neuronal traits must rely on previously unexplored mechanisms operating downstream from proneural bHLH proteins. Here we show that the HMG-box transcription factors Sox4 and Sox11 are of critical importance, downstream from proneural bHLH proteins, for the establishment of pan-neuronal protein expression. Examination of a neuronal gene promoter reveals that Sox4 and Sox11 exert their functions as transcriptional activators. Interestingly, the capacity of Sox4 and Sox11 to induce the expression of neuronal traits is independent of mechanisms regulating the exit of neural progenitors from the cell cycle. The transcriptional repressor protein REST/NRSF has been demonstrated to block neuronal gene expression in undifferentiated neural cells. We now show that REST/NRSF restricts the expression of Sox4 and Sox11, explaining how REST/NRSF can prevent precocious expression of neuronal proteins. Together, these findings demonstrate a central regulatory role of Sox4 and Sox11 during neuronal maturation and mechanistically separate cell cycle withdrawal from the establishment of neuronal properties.
  •  
12.
  • Bjorkman, A, et al. (författare)
  • Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution
  • 2020
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 34:15-16, s. 1065-1074
  • Tidskriftsartikel (refereegranskat)abstract
    • RTEL1 helicase is a component of DNA repair and telomere maintenance machineries. While RTEL1's role in DNA replication is emerging, how RTEL1 preserves genomic stability during replication remains elusive. Here we used a range of proteomic, biochemical, cell, and molecular biology and gene editing approaches to provide further insights into potential role(s) of RTEL1 in DNA replication and genome integrity maintenance. Our results from complementary human cell culture models established that RTEL1 and the Polδ subunit Poldip3 form a complex and are/function mutually dependent in chromatin binding after replication stress. Loss of RTEL1 and Poldip3 leads to marked R-loop accumulation that is confined to sites of active replication, enhances endogenous replication stress, and fuels ensuing genomic instability. The impact of depleting RTEL1 and Poldip3 is epistatic, consistent with our proposed concept of these two proteins operating in a shared pathway involved in DNA replication control under stress conditions. Overall, our data highlight a previously unsuspected role of RTEL1 and Poldip3 in R-loop suppression at genomic regions where transcription and replication intersect, with implications for human diseases including cancer.
  •  
13.
  • Buza-Vidas, Natalija, et al. (författare)
  • Cytokines regulate postnatal hematopoietic stem cell expansion : Opposing roles of thrombopoietin and LNK
  • 2006
  • Ingår i: Genes & Development. - Woodbury, NY, USA : Cold Spring Harbor Laboratory Press (CSHL). - 0890-9369 .- 1549-5477. ; 20:15, s. 2018-2023
  • Tidskriftsartikel (refereegranskat)abstract
    • The role of cytokines as regulators of hematopoietic stem cell (HSC) expansion remains elusive. Herein, we identify thrombopoietin (THPO) and the cytokine signaling inhibitor LNK, as opposing physiological regulators of HSC expansion. Lnk(-/-) HSCs continue to expand postnatally, up to 24-fold above normal by 6 mo of age. Within the stem cell compartment, this expansion is highly selective for self-renewing long-term HSCs (LT-HSCs), which show enhanced THPO responsiveness. Lnk(-/-) HSC expansion is dependent on THPO, and 12-wk-old Lnk(-/-)Thpo(-/-) mice have 65-fold fewer LT-HSCs than Lnk(-/-) mice. Expansions of multiple myeloid, but not lymphoid, progenitors in Lnk(-/-) mice also proved THPO-dependent.
  •  
14.
  • Calvo, Charles-Félix, et al. (författare)
  • Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis.
  • 2011
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 25:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capillary endothelial cells in the subventricular zone (SVZ) of the brain. Functionally, members of the vascular endothelial growth factor (VEGF) family can stimulate neurogenesis as well as angiogenesis, but it has been unclear whether they act directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from angiogenic capillaries. Here, we show that VEGFR-3, a receptor required for lymphangiogenesis, is expressed by NSCs and is directly required for neurogenesis. Vegfr3:YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated by the VEGFR-3 ligand VEGF-C in vitro. Overexpression of VEGF-C stimulates VEGFR-3-expressing NSCs and neurogenesis in the SVZ without affecting angiogenesis. Conversely, conditional deletion of Vegfr3 in neural cells, inducible deletion in subventricular astrocytes, and blocking of VEGFR-3 signaling with antibodies reduce SVZ neurogenesis. Therefore, VEGF-C/VEGFR-3 signaling acts directly on NSCs and regulates adult neurogenesis, opening potential approaches for treatment of neurodegenerative diseases.
  •  
15.
  • Cantù, Claudio, et al. (författare)
  • Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/beta-catenin signaling
  • 2018
  • Ingår i: Genes & Development. - : COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. - 0890-9369 .- 1549-5477. ; 32:21-22, s. 1443-1458
  • Tidskriftsartikel (refereegranskat)abstract
    • Bcl9 and Pygopus (Pygo) are obligate Wnt/beta-catenin cofactors in Drosophila, yet their contribution to Wnt signaling during vertebrate development remains unresolved. Combining zebrafish and mouse genetics, we document a conserved, beta-catenin-associated function for BCL9 and Pygo proteins during vertebrate heart development. Disrupting the beta-catenin-BCL9-Pygo complex results in a broadly maintained canonical Wnt response yet perturbs heart development and proper expression of key cardiac regulators. Our work highlights BCL9 and Pygo as selective beta-catenin cofactors in a subset of canonical Wnt responses during vertebrate development. Moreover, our results implicate alterations in BCL9 and BCL9L in human congenital heart defects.
  •  
16.
  • Cantù, Claudio, et al. (författare)
  • Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development.
  • 2014
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 28:17, s. 1879-84
  • Tidskriftsartikel (refereegranskat)abstract
    • Bcl9 and Bcl9l (Bcl9/9l) encode Wnt signaling components that mediate the interaction between β-catenin and Pygopus (Pygo) via two evolutionarily conserved domains, HD1 and HD2, respectively. We generated mouse strains lacking these domains to probe the β-catenin-dependent and β-catenin-independent roles of Bcl9/9l and Pygo during mouse development. While lens development is critically dependent on the presence of the HD1 domain, it is not affected by the lack of the HD2 domain, indicating that Bcl9/9l act in this context in a β-catenin-independent manner. Furthermore, we uncover a new regulatory circuit in which Pax6, the master regulator of eye development, directly activates Bcl9/9l transcription.
  •  
17.
  • Chang, C, et al. (författare)
  • A laminin 511 matrix is regulated by TAZ and functions as the ligand for the α6Bβ1 integrin to sustain breast cancer stem cells
  • 2015
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 29:1, s. 1-6
  • Tidskriftsartikel (refereegranskat)abstract
    • Understanding how the extracellular matrix impacts the function of cancer stem cells (CSCs) is a significant but poorly understood problem. We report that breast CSCs produce a laminin (LM) 511 matrix that promotes self-renewal and tumor initiation by engaging the α6Bβ1 integrin and activating the Hippo transducer TAZ. Although TAZ is important for the function of breast CSCs, the mechanism is unknown. We observed that TAZ regulates the transcription of the α5 subunit of LM511 and the formation of a LM511 matrix. These data establish a positive feedback loop involving TAZ and LM511 that contributes to stemness in breast cancer.
  •  
18.
  • Davies, RC, et al. (författare)
  • WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes
  • 1998
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 12:20, s. 3217-3225
  • Tidskriftsartikel (refereegranskat)abstract
    • WT1 is essential for normal kidney development, and genetic alterations are associated with Wilms’ tumor, Denys Drash (DDS), and Frasier syndromes. Although generally considered a transcription factor this study has revealed that WT1 interacts with an essential splicing factor, U2AF65, and associates with the splicing machinery. WT1 is alternatively spliced and isoforms that include three amino acids, KTS, show stronger interaction with U2AF65 in vitro and better colocalization with splicing factors in vivo. Interestingly a mutation associated with DDS enhanced both −KTS WT1 binding to U2AF65 and splicing-factor colocalization. These data illustrate the functional importance of WT1 isoforms and suggest that WT1 plays a role in pre-mRNA splicing.
  •  
19.
  • de Vries, FAT, et al. (författare)
  • Mouse Sycp1 functions in synaptonemal complex assembly, meiotic recombination, and XY body formation
  • 2005
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 19:11, s. 1376-1389
  • Tidskriftsartikel (refereegranskat)abstract
    • In meiotic prophase, synaptonemal complexes (SCs) closely appose homologous chromosomes (homologs) along their length. SCs are assembled from two axial elements (AEs), one along each homolog, which are connected by numerous transverse filaments (TFs). We disrupted the mouse gene encoding TF protein Sycp1 to analyze the role of TFs in meiotic chromosome behavior and recombination. Sycp1-/- mice are infertile, but otherwise healthy. Sycp1-/- spermatocytes form normal AEs, which align homologously, but do not synapse. Most Sycp1-/- spermatocytes arrest in pachynema, whereas a small proportion reaches diplonema, or, exceptionally, metaphase I. In leptotene Sycp1-/- spermatocytes, γH2AX (indicative of DNA damage, including double-strand breaks) appears normal. In pachynema, Sycp1-/- spermatocytes display a number of discrete γH2AX domains along each chromosome, whereas γH2AX disappears from autosomes in wild-type spermatocytes. RAD51/DMC1, RPA, and MSH4 foci (which mark early and intermediate steps in pairing/recombination) appear in similar numbers as in wild type, but do not all disappear, and MLH1 and MLH3 foci (which mark late steps in crossing over) are not formed. Crossovers were rare in metaphase I of Sycp1-/- mice. We propose that SYCP1 has a coordinating role, and ensures formation of crossovers. Unexpectedly, Sycp1-/- spermatocytes did not form XY bodies.
  •  
20.
  • Djupedal, Ingela, et al. (författare)
  • RNA Pol II subunit Rpb7 promotes centromeric transcription and RNAi-directed chromatin silencing
  • 2005
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 19:19, s. 2301-2306
  • Tidskriftsartikel (refereegranskat)abstract
    • Fission yeast centromeric repeats are transcribed into small interfering RNA (siRNA) precursors (pre-siRNAs), which are processed by Dicer to direct heterochromatin formation. Recently, Rpb1 and Rpb2 subunits of RNA polymerase II (RNA Pol II) were shown to mediate RNA interference (RNAi)-directed chromatin modification but did not affect pre-siRNA levels. Here we show that another Pol II subunit, Rpb7 has a specific role in presiRNA transcription. We define a centromeric presiRNA promoter from which initiation is exquisitely sensitive to the rpb7-G150D mutation. In contrast to other Pol II subunits, Rpb7 promotes pre-siRNA transcription required for RNAi-directed chromatin silencing.
  •  
21.
  • Do, DV, et al. (författare)
  • A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo
  • 2013
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 27:12, s. 1378-1390
  • Tidskriftsartikel (refereegranskat)abstract
    • Although it is known that OCT4–NANOG are required for maintenance of pluripotent cells in vitro, the upstream signals that regulate this circuit during early development in vivo have not been identified. Here we demonstrate, for the first time, signal transducers and activators of transcription 3 (STAT3)-dependent regulation of the OCT4–NANOG circuitry necessary to maintain the pluripotent inner cell mass (ICM), the source of in vitro-derived embryonic stem cells (ESCs). We show that STAT3 is highly expressed in mouse oocytes and becomes phosphorylated and translocates to the nucleus in the four-cell and later stage embryos. Using leukemia inhibitory factor (Lif)-null embryos, we found that STAT3 phosphorylation is dependent on LIF in four-cell stage embryos. In blastocysts, interleukin 6 (IL-6) acts in an autocrine fashion to ensure STAT3 phosphorylation, mediated by janus kinase 1 (JAK1), a LIF- and IL-6-dependent kinase. Using genetically engineered mouse strains to eliminate Stat3 in oocytes and embryos, we firmly establish that STAT3 is essential for maintenance of ICM lineages but not for ICM and trophectoderm formation. Indeed, STAT3 directly binds to the Oct4 and Nanog distal enhancers, modulating their expression to maintain pluripotency of mouse embryonic and induced pluripotent stem cells. These results provide a novel genetic model of cell fate determination operating through STAT3 in the preimplantation embryo and pluripotent stem cells in vivo.
  •  
22.
  • Eichmann, Anne, et al. (författare)
  • Neural guidance molecules regulate vascular remodeling and vessel navigation.
  • 2005
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 19:9
  • Tidskriftsartikel (refereegranskat)abstract
    • The development of the embryonic blood vascular and lymphatic systems requires the coordinated action of several transcription factors and growth factors that target endothelial and periendothelial cells. However, according to recent studies, the precise "wiring" of the vascular system does not occur without an ordered series of guidance decisions involving several molecules initially discovered for axons in the nervous system, including ephrins, netrins, slits, and semaphorins. Here, we summarize the new advances in our understanding of the roles of these axonal pathfinding molecules in vascular remodeling and vessel guidance, indicating that neuronal axons and vessel sprouts use common molecular mechanisms for navigation in the body.
  •  
23.
  • Engblom, David, et al. (författare)
  • Direct glucocorticoid receptor-Stat5 interaction in hepatocytes controls body size and maturation-related gene expression
  • 2007
  • Ingår i: Genes & Development. - : Csh Cold Spring Harbor Laboratory Press. - 0890-9369 .- 1549-5477. ; 21:10, s. 1157-1162
  • Tidskriftsartikel (refereegranskat)abstract
    • The glucocorticoid receptor regulates transcription through DNA binding as well as through cross-talk with other transcription factors. In hepatocytes, the glucocorticoid receptor is critical for normal postnatal growth. Using hepatocyte- specific and domain-selective mutations in the mouse we show that Stat5 in hepatocytes is essential for normal postnatal growth and that it mediates the growth- promoting effect of the glucocorticoid receptor through a direct interaction involving the N-terminal tetramerization domain of Stat5b. This interaction mediates a selective and unexpectedly extensive part of the transcriptional actions of these molecules since it controls the expression of gene sets involved in growth and sexual maturation.
  •  
24.
  • Erjavec, Nika, 1977, et al. (författare)
  • Accelerated aging and failure to segregate damaged proteins in Sir2 mutants can be suppressed by overproducing the protein aggregation-remodeling factor Hsp104p
  • 2007
  • Ingår i: GENES & DEVELOPMENT. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 21:19, s. 2410-2421
  • Tidskriftsartikel (refereegranskat)abstract
    • The levels of oxidatively damaged, carbonylated, proteins increase with the replicative age of yeast mother cells. We show here that such carbonylated proteins are associated with Hsp104p-containing protein aggregates and that these aggregates, like oxidized proteins, are retained in the progenitor cell during cytokinesis by a Sir2p-dependent process. Deletion of HSP104 resulted in a breakdown of damage asymmetry, and overproduction of Hsp104p partially restored damage retention in sir2Δ cells, suggesting that functional chaperones associated with protein aggregates are required for the establishment of damage asymmetry and that these functions are limited in sir2Δ cells. In line with this, Hsp104p and several Hsp70s displayed elevated damaged in sir2Δ cells, and protein aggregates were rescued at a slower rate in this mutant. Moreover, overproduction of Hsp104p suppressed the accelerated aging of cells lacking Sir2p, and drugs inhibiting damage segregation further demonstrated that spatial quality control is required to rejuvenate the progeny.
  •  
25.
  • Fell, SM, et al. (författare)
  • Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA
  • 2017
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 31:10, s. 1036-1053
  • Tidskriftsartikel (refereegranskat)abstract
    • We recently identified pathogenic KIF1Bβ mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted KIF1Bβ in the mouse sympathetic nervous system and observed impaired sympathetic nervous function and misexpression of genes required for sympathoadrenal lineage differentiation. We discovered that KIF1Bβ is required for nerve growth factor (NGF)-dependent neuronal differentiation through anterograde transport of the NGF receptor TRKA. Moreover, pathogenic KIF1Bβ mutations identified in neuroblastoma impair TRKA transport. Expression of neuronal differentiation markers is ablated in both KIF1Bβ-deficient mouse neuroblasts and human neuroblastomas that lack KIF1Bβ. Transcriptomic analyses show that unfavorable neuroblastomas resemble mouse sympathetic neuroblasts lacking KIF1Bβ independent of MYCN amplification and the loss of genes neighboring KIF1B on chromosome 1p36. Thus, defective precursor cell differentiation, a common trait of aggressive childhood malignancies, is a pathogenic effect of KIF1Bβ loss in neuroblastomas. Furthermore, neuropathy-associated KIF1Bβ mutations impede cargo transport, providing a direct link between neuroblastomas and neurodegeneration.
  •  
26.
  • Fender, Aurelie, et al. (författare)
  • RNAs actively cycle on the Sm-like protein Hfq
  • 2010
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 24:23, s. 2621-2626
  • Tidskriftsartikel (refereegranskat)abstract
    • Hfq, a protein required for small RNA (sRNA)-mediated regulation in bacteria, binds RNA with low-nanomolar K-d values and long half-lives of complexes (>100 min). This cannot be reconciled with the 1-2-min response time of regulation in vivo. We show that RNAs displace each other on Hfq on a short time scale by RNA concentration-driven (active) cycling. Already at submicromolar concentrations of competitor RNA, half-lives of RNA-Hfq complexes are approximate to 1 min. We propose that competitor RNA associates transiently with RNA-Hfq complexes, RNAs exchange binding sites, and one of the RNAs eventually dissociates. This solves the "strong binding-high turn-over" paradox and permits efficient use of the Hfq pool.
  •  
27.
  •  
28.
  • Fredriksson, Åsa, 1968, et al. (författare)
  • Decline in ribosomal fidelity contributes to the accumulation and stabilization of the master stress response regulator sigma S upon carbon starvation
  • 2007
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 21:7, s. 862-874
  • Tidskriftsartikel (refereegranskat)abstract
    • The {sigma}S subunit of RNA polymerase is a master regulator of Escherichia coli that retards cellular senescence and bestows cells with general stress protective functions during growth arrest. We show that mutations and drugs triggering translational errors elevate {sigma}S levels and stability. Furthermore, mutations enhancing translational fidelity attenuate induction of the rpoS regulon and prevent stabilization of {sigma}S upon carbon starvation. Destabilization of {sigma}S by increased proofreading requires the presence of the {sigma}S recognition factor SprE (RssB) and the ClpXP protease. The data further suggest that {sigma}S becomes stabilized upon starvation as a result of ClpP sequestration and this sequestration is enhanced by oxidative modifications of aberrant proteins produced by erroneous translation. ClpP overproduction counteracted starvation-induced stabilization of {sigma}S, whereas overproduction of a ClpXP substrate (ssrA-tagged GFP) stabilized {sigma}S in exponentially growing cells. We present a model for the sequence of events leading to the accumulation and activation of {sigma}S upon carbon starvation, which are linked to alterations in both ribosomal fidelity and efficiency.
  •  
29.
  • Garg, Parie, et al. (författare)
  • Idling by DNA polymerase delta maintains a ligatable nick during lagging-strand DNA replication.
  • 2004
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 18:22, s. 2764-2773
  • Tidskriftsartikel (refereegranskat)abstract
    • During each yeast cell cycle, ∼100,000 nicks are generated during lagging-strand DNA replication. Efficient nick processing during Okazaki fragment maturation requires the coordinated action of DNA polymerase δ (Pol δ) and the FLAP endonuclease FEN1. Misregulation of this process leads to the accumulation of double-stranded breaks and cell lethality. Our studies highlight a remarkably efficient mechanism for Okazaki fragment maturation in which Pol δ by default displaces 2–3 nt of any downstream RNA or DNA it encounters. In the presence of FEN1, efficient nick translation ensues, whereby a mixture of mono- and small oligonucleotides are released. If FEN1 is absent or not optimally functional, the ability of Pol δ to back up via its 3′–5′-exonuclease activity, a process called idling, maintains the polymerase at a position that is ideal either for ligation (in case of a DNA–DNA nick) or for subsequent engagement by FEN1 (in case of a DNA–RNA nick). Consistent with the hypothesis that DNA polymerase ϵ is the leading-strand enzyme, we observed no idling by this enzyme and no cooperation with FEN1 for creating a ligatable nick.
  •  
30.
  • Gatfield, David, et al. (författare)
  • Integration of microRNA miR-122 in hepatic circadian gene expression
  • 2009
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory Press (CSHL). - 0890-9369 .- 1549-5477. ; 23:11, s. 1313-26
  • Tidskriftsartikel (refereegranskat)abstract
    • In liver, most metabolic pathways are under circadian control, and hundreds of protein-encoding genes are thus transcribed in a cyclic fashion. Here we show that rhythmic transcription extends to the locus specifying miR-122, a highly abundant, hepatocyte-specific microRNA. Genetic loss-of-function and gain-of-function experiments have identified the orphan nuclear receptor REV-ERBalpha as the major circadian regulator of mir-122 transcription. Although due to its long half-life mature miR-122 accumulates at nearly constant rates throughout the day, this miRNA is tightly associated with control mechanisms governing circadian gene expression. Thus, the knockdown of miR-122 expression via an antisense oligonucleotide (ASO) strategy resulted in the up- and down-regulation of hundreds of mRNAs, of which a disproportionately high fraction accumulates in a circadian fashion. miR-122 has previously been linked to the regulation of cholesterol and lipid metabolism. The transcripts associated with these pathways indeed show the strongest time point-specific changes upon miR-122 depletion. The identification of Pparbeta/delta and the peroxisome proliferator-activated receptor alpha (PPARalpha) coactivator Smarcd1/Baf60a as novel miR-122 targets suggests an involvement of the circadian metabolic regulators of the PPAR family in miR-122-mediated metabolic control.
  •  
31.
  •  
32.
  • Göthe, Sten, et al. (författare)
  • Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation.
  • 1999
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369. ; 13:10, s. 1329-41
  • Tidskriftsartikel (refereegranskat)abstract
    • Thyroid hormone (T3) has widespread functions in development and homeostasis, although the receptor pathways by which this diversity arises are unclear. Deletion of the T3 receptors TRalpha1 or TRbeta individually reveals only a small proportion of the phenotypes that arise in hypothyroidism, implying that additional pathways must exist. Here, we demonstrate that mice lacking both TRalpha1 and TRbeta (TRalpha1(-/-)beta-/-) display a novel array of phenotypes not found in single receptor-deficient mice, including an extremely hyperactive pituitary-thyroid axis, poor female fertility and retarded growth and bone maturation. These results establish that major T3 actions are mediated by common pathways in which TRalpha1 and TRbeta cooperate with or substitute for each other. Thus, varying the balance of use of TRalpha1 and TRbeta individually or in combination facilitates control of an extended spectrum of T3 actions. There was no evidence for any previously unidentified T3 receptors in TRalpha1(-/-)beta-/- mouse tissues. Compared to the debilitating symptoms of severe hypothyroidism, the milder overall phenotype of TRalpha1(-/-)beta-/- mice, lacking all known T3 receptors, indicates divergent consequences for hormone versus receptor deficiency. These distinctions suggest that T3-independent actions of T3 receptors, demonstrated previously in vitro, may be a significant function in vivo.
  •  
33.
  •  
34.
  • Henriksson, S, et al. (författare)
  • The scaffold protein WRAP53β orchestrates the ubiquitin response critical for DNA double-strand break repair
  • 2014
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 28:24, s. 2726-2738
  • Tidskriftsartikel (refereegranskat)abstract
    • The WD40 domain-containing protein WRAP53β (WD40 encoding RNA antisense to p53; also referred to as WDR79/TCAB1) controls trafficking of splicing factors and the telomerase enzyme to Cajal bodies, and its functional loss has been linked to carcinogenesis, premature aging, and neurodegeneration. Here, we identify WRAP53β as an essential regulator of DNA double-strand break (DSB) repair. WRAP53β rapidly localizes to DSBs in an ATM-, H2AX-, and MDC1-dependent manner. We show that WRAP53β targets the E3 ligase RNF8 to DNA lesions by facilitating the interaction between RNF8 and its upstream partner, MDC1, in response to DNA damage. Simultaneous binding of MDC1 and RNF8 to the highly conserved WD40 scaffold domain of WRAP53β facilitates their interaction and accumulation of RNF8 at DSBs. In this manner, WRAP53β controls proper ubiquitylation at DNA damage sites and the downstream assembly of 53BP1, BRCA1, and RAD51. Furthermore, we reveal that knockdown of WRAP53β impairs DSB repair by both homologous recombination (HR) and nonhomologous end-joining (NHEJ), causes accumulation of spontaneous DNA breaks, and delays recovery from radiation-induced cell cycle arrest. Our findings establish WRAP53β as a novel regulator of DSB repair by providing a scaffold for DNA repair factors.
  •  
35.
  • Holmberg, J, et al. (författare)
  • Ephrin-A2 reverse signaling negatively regulates neural progenitor proliferation and neurogenesis
  • 2005
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 19:4, s. 462-471
  • Tidskriftsartikel (refereegranskat)abstract
    • The number of cells in an organ is regulated by mitogens and trophic factors that impinge on intrinsic determinants of proliferation and apoptosis. We here report the identification of an additional mechanism to control cell number in the brain: EphA7 induces ephrin-A2 reverse signaling, which negatively regulates neural progenitor cell proliferation. Cells in the neural stem cell niche in the adult brain proliferate more and have a shorter cell cycle in mice lacking ephrin-A2. The increased progenitor proliferation is accompanied by a higher number of cells in the olfactory bulb. Disrupting the interaction between ephrin-A2 and EphA7 in the adult brain of wild-type mice disinhibits proliferation and results in increased neurogenesis. The identification of ephrin-A2 and EphA7 as negative regulators of progenitor cell proliferation reveals a novel mechanism to control cell numbers in the brain.
  •  
36.
  • Hu, Yeguang, et al. (författare)
  • Superenhancer reprogramming drives a B-cell-epithelial transition and high-risk leukemia
  • 2016
  • Ingår i: Genes & Development. - : COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. - 0890-9369 .- 1549-5477. ; 30:17, s. 1971-1990
  • Tidskriftsartikel (refereegranskat)abstract
    • IKAROS is required for the differentiation of highly proliferative pre-B-cell precursors, and loss of IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of superenhancers with distinct lineage affiliations. IKAROS defines superenhancers at pre-B-cell differentiation genes together with B-cell master regulators such as PAX5, EBF1, and IRF4 but is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors. IKAROS is also highly enriched at inactive enhancers of genes normally expressed in stem-epithelial cells. Upon IKAROS loss, expression of pre-B-cell differentiation genes is attenuated, while a group of extralineage transcription factors that are directly repressed by IKAROS and depend on EBF1 relocalization at their enhancers for expression is induced. LHX2, LMO2, and TEAD-YAP1, normally kept separate from native B-cell transcription regulators by IKAROS, now cooperate directly with them in a de novo superenhancer network with its own feed-forward transcriptional reinforcement. Induction of de novo superenhancers antagonizes Polycomb repression and superimposes aberrant stem epithelial cell properties in a B-cell precursor. This dual mechanism of IKAROS regulation promotes differentiation while safeguarding against a hybrid stem epithelial B-cell phenotype that underlies high-risk B-ALL.
  •  
37.
  • Ishiguro, K, et al. (författare)
  • Meiosis-specific cohesin mediates homolog recognition in mouse spermatocytes
  • 2014
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 28:6, s. 594-607
  • Tidskriftsartikel (refereegranskat)abstract
    • During meiosis, homologous chromosome (homolog) pairing is promoted by several layers of regulation that include dynamic chromosome movement and meiotic recombination. However, the way in which homologs recognize each other remains a fundamental issue in chromosome biology. Here, we show that homolog recognition or association initiates upon entry into meiotic prophase before axis assembly and double-strand break (DSB) formation. This homolog association develops into tight pairing only during or after axis formation. Intriguingly, the ability to recognize homologs is retained in Sun1 knockout spermatocytes, in which telomere-directed chromosome movement is abolished, and this is the case even in Spo11 knockout spermatocytes, in which DSB-dependent DNA homology search is absent. Disruption of meiosis-specific cohesin RAD21L precludes the initial association of homologs as well as the subsequent pairing in spermatocytes. These findings suggest the intriguing possibility that homolog recognition is achieved primarily by searching for homology in the chromosome architecture as defined by meiosis-specific cohesin rather than in the DNA sequence itself.
  •  
38.
  • Jakobsen, J. S., et al. (författare)
  • Temporal ChIP-on-chip reveals Biniou as a universal regulator of the visceral muscle transcriptional network
  • 2007
  • Ingår i: Genes Dev. - : Cold Spring Harbor Laboratory. - 0890-9369. ; 21:19, s. 2448-60
  • Tidskriftsartikel (refereegranskat)abstract
    • Smooth muscle plays a prominent role in many fundamental processes and diseases, yet our understanding of the transcriptional network regulating its development is very limited. The FoxF transcription factors are essential for visceral smooth muscle development in diverse species, although their direct regulatory role remains elusive. We present a transcriptional map of Biniou (a FoxF transcription factor) and Bagpipe (an Nkx factor) activity, as a first step to deciphering the developmental program regulating Drosophila visceral muscle development. A time course of chromatin immunoprecipitatation followed by microarray analysis (ChIP-on-chip) experiments and expression profiling of mutant embryos reveal a dynamic map of in vivo bound enhancers and direct target genes. While Biniou is broadly expressed, it regulates enhancers driving temporally and spatially restricted expression. In vivo reporter assays indicate that the timing of Biniou binding is a key trigger for the time span of enhancer activity. Although bagpipe and biniou mutants phenocopy each other, their regulatory potential is quite different. This network architecture was not apparent from genetic studies, and highlights Biniou as a universal regulator in all visceral muscle, regardless of its developmental origin or subsequent function. The regulatory connection of a number of Biniou target genes is conserved in mice, suggesting an ancient wiring of this developmental program.
  •  
39.
  • Jang, Seongmin, et al. (författare)
  • Structural basis of recognition and destabilization of the histone H2B ubiquitinated nucleosome by the DOT1L histone H3 Lys79 methyltransferase
  • 2019
  • Ingår i: Genes & Development. - : NLM (Medline). - 0890-9369 .- 1549-5477. ; 33:11-12, s. 620-625
  • Tidskriftsartikel (refereegranskat)abstract
    • DOT1L is a histone H3 Lys79 methyltransferase whose activity is stimulated by histone H2B Lys120 ubiquitination, suggesting cross-talk between histone H3 methylation and H2B ubiquitination. Here, we present cryo-EM structures of DOT1L complexes with unmodified or H2B ubiquitinated nucleosomes, showing that DOT1L recognizes H2B ubiquitin and the H2A/H2B acidic patch through a C-terminal hydrophobic helix and an arginine anchor in DOT1L, respectively. Furthermore, the structures combined with single-molecule FRET experiments show that H2B ubiquitination enhances a noncatalytic function of the DOT1L-destabilizing nucleosome. These results establish the molecular basis of the cross-talk between H2B ubiquitination and H3 Lys79 methylation as well as nucleosome destabilization by DOT1L.
  •  
40.
  • Jiang, Hua, et al. (författare)
  • Ectopic application of the repressive histone modification H3K9me2 establishes post-zygotic reproductive isolation in Arabidopsis Thaliana
  • 2017
  • Ingår i: Genes and Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 31, s. 1272-1287
  • Tidskriftsartikel (refereegranskat)abstract
    • Hybrid seed lethality as a consequence of interspecies or interploidy hybridizations is a major mechanism of reproductive isolation in plants. This mechanism is manifested in the endosperm, a dosage-sensitive tissue supporting embryo growth. Deregulated expression of imprinted genes such as ADMETOS (ADM) underpin the interploidy hybridization barrier in Arabidopsis thaliana; however, the mechanisms of their action remained unknown. In this study, we show that ADM interacts with the AT hook domain protein AHL10 and the SET domain-containing SU (VAR) 3-9 homolog SUVH9 and ectopically recruits the heterochromatic mark H3K9me2 to AT-rich transposable elements (TEs), causing deregulated expression of neighboring genes. Several hybrid incompatibility genes identified in Drosophila encode for dosage-sensitive heterochromatin-interacting proteins, which has led to the suggestion that hybrid incompatibilities evolve as a consequence of interspecies divergence of selfish DNA elements and their regulation. Our data show that imbalance of dosage-sensitive chromatin regulators underpins the barrier to interploidy hybridization in Arabidopsis, suggesting that reproductive isolation as a consequence of epigenetic regulation of TEs is a conserved feature in animals and plants.
  •  
41.
  • Jiang, Hai, et al. (författare)
  • The combined status of ATM and p53 link tumor development with therapeutic response
  • 2009
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 23:16, s. 1895-1909
  • Tidskriftsartikel (refereegranskat)abstract
    • While the contribution of specific tumor suppressor networks to cancer development has been the subject of considerable recent study, it remains unclear how alterations in these networks are integrated to influence the response of tumors to anti-cancer treatments. Here, we show that mechanisms commonly used by tumors to bypass early neoplastic checkpoints ultimately determine chemotherapeutic response and generate tumor-specific vulnerabilities that can be exploited with targeted therapies. Specifically, evaluation of the combined status of ATM and p53, two commonly mutated tumor suppressor genes, can help to predict the clinical response to genotoxic chemotherapies. We show that in p53-deficient settings, suppression of ATM dramatically sensitizes tumors to DNA-damaging chemotherapy, whereas, conversely, in the presence of functional p53, suppression of ATM or its downstream target Chk2 actually protects tumors from being killed by genotoxic agents. Furthermore, ATM-deficient cancer cells display strong nononcogene addiction to DNA-PKcs for survival after DNA damage, such that suppression of DNA-PKcs in vivo resensitizes inherently chemoresistant ATM-deficient tumors to genotoxic chemotherapy. Thus, the specific set of alterations induced during tumor development plays a dominant role in determining both the tumor response to conventional chemotherapy and specific susceptibilities to targeted therapies in a given malignancy.
  •  
42.
  • Jishage, Miki, et al. (författare)
  • Regulation of sigma factor competition by the alarmone ppGpp
  • 2002
  • Ingår i: Genes & Development. - : CSH Press. - 0890-9369 .- 1549-5477. ; 16:10, s. 1260-1270
  • Tidskriftsartikel (refereegranskat)abstract
    • Many regulons controlled by alternative ç factors, including çs and ç32, are poorly induced in cells lacking the alarmone ppGpp. We show that ppGpp is not absolutely required for the activity of çs-dependent promoters because underproduction of ç70, specific mutations in rpoD (rpoD40 and rpoD35), or overproduction of Rsd (anti-ç70) restored expression from çs-dependent promoters in vivo in the absence of ppGpp accumulation. An in vitro transcription/competition assay with reconstituted RNA polymerase showed that addition of ppGpp reduces the ability of wild-type ç70 to compete with ç32 for core binding and the mutant ç70 proteins, encoded by rpoD40 and rpoD35, compete less efficiently than wild-type ç70. Similarly, an in vivo competition assay showed that the ability of both sigma(32) and sigma(S) to compete with sigma(70) is diminished in cells lacking ppGpp. Consistently, the fraction of çs and ç32 bound to core was drastically reduced in ppGpp-deficient cells. Thus, the stringent response encompasses a mechanism that alters the relative competitiveness of sigma factors in accordance with cellular demands during physiological stress.
  •  
43.
  • Johansson, Marcus JO, et al. (författare)
  • Nonsense-mediated mRNA decay maintains translational fidelity by limiting magnesium uptake
  • 2010
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 24:14, s. 1491-1495
  • Tidskriftsartikel (refereegranskat)abstract
    • Inactivation of the yeast nonsense-mediated mRNA decay (NMD) pathway stabilizes nonsense mRNAs and promotes readthrough of premature translation termination codons. Although the latter phenotype is thought to reflect a direct role of NMD factors in translation termination, its mechanism is unknown. Here we show that the reduced termination efficiency of NMD-deficient cells is attributable to increased expression of the magnesium transporter Alr1p and the resulting effects of elevated Mg2+ levels on termination fidelity. Alr1p levels increase because an upstream ORF in ALR1 mRNA targets the transcript for NMD. Our results demonstrate that NMD, at least in yeast, controls Mg2+ homeostasis and, consequently, translational fidelity.
  •  
44.
  • Kelly, GL, et al. (författare)
  • Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53
  • 2014
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 28:1, s. 58-70
  • Tidskriftsartikel (refereegranskat)abstract
    • The transcriptional regulator c-MYC is abnormally overexpressed in many human cancers. Evasion from apoptosis is critical for cancer development, particularly c-MYC-driven cancers. We explored which anti-apoptotic BCL-2 family member (expressed under endogenous regulation) is essential to sustain c-MYC-driven lymphoma growth to reveal which should be targeted for cancer therapy. Remarkably, inducible Cre-mediated deletion of even a single Mcl-1 allele substantially impaired the growth of c-MYC-driven mouse lymphomas. Mutations in p53 could diminish but not obviate the dependency of c-MYC-driven mouse lymphomas on MCL-1. Importantly, targeting of MCL-1 killed c-MYC-driven human Burkitt lymphoma cells, even those bearing mutations in p53. Given that loss of one allele of Mcl-1 is well tolerated in healthy tissues, our results suggest that therapeutic targeting of MCL-1 would be an attractive therapeutic strategy for MYC-driven cancers.
  •  
45.
  • Knudsen, Kasper Jermiin, et al. (författare)
  • ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation.
  • 2015
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 29:18, s. 1915-1929
  • Tidskriftsartikel (refereegranskat)abstract
    • The balance between self-renewal and differentiation is crucial for the maintenance of hematopoietic stem cells (HSCs). Whereas numerous gene regulatory factors have been shown to control HSC self-renewal or drive their differentiation, we have relatively few insights into transcription factors that serve to restrict HSC differentiation. In the present work, we identify ETS (E-twenty-six)-related gene (ERG) as a critical factor protecting HSCs from differentiation. Specifically, loss of Erg accelerates HSC differentiation by >20-fold, thus leading to rapid depletion of immunophenotypic and functional HSCs. Molecularly, we could demonstrate that ERG, in addition to promoting the expression of HSC self-renewal genes, also represses a group of MYC targets, thereby explaining why Erg loss closely mimics Myc overexpression. Consistently, the BET domain inhibitor CPI-203, known to repress Myc expression, confers a partial phenotypic rescue. In summary, ERG plays a critical role in coordinating the balance between self-renewal and differentiation of HSCs.
  •  
46.
  • Kullander, Klas, et al. (författare)
  • Ephrin-B3 is the midline barrier that prevents corticospinal tract axons from recrossing, allowing for unilateral motor control
  • 2001
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 15:7, s. 877-888
  • Tidskriftsartikel (refereegranskat)abstract
    • Growing axons follow highly stereotypical pathways, guided by a variety of attractive and repulsive cues, before establishing specific connections with distant targets. A particularly well-known example that illustrates the complexity of axonal migration pathways involves the axonal projections of motor neurons located in the motor cortex. These projections take a complex route during which they first cross the midline, then form the corticospinal tract, and ultimately connect with motor neurons in the contralateral side of the spinal cord. These obligatory contralateral connections account for why one side of the brain controls movement on the opposing side of the body. The netrins and slits provide well-known midline signals that regulate axonal crossings at the midline. Herein we report that a member of the ephrin family, ephrin-B3, also plays a key role at the midline to regulate axonal crossing. In particular, we show that ephrin-B3 acts as the midline barrier that prevents corticospinal tract projections from recrossing when they enter the spinal gray matter. We report that in ephrin-B3(-/-) mice, corticospinal tract projections freely recross in the spinal gray matter, such that the motor cortex on one side of the brain now provides bilateral input to the spinal cord. This neuroanatomical abnormality in ephrin-B3(-/-) mice correlates with loss of unilateral motor control, yielding mice that simultaneously move their right and left limbs and thus have a peculiar hopping gait quite unlike the alternate step gait displayed by normal mice. The corticospinal and walking defects in ephrin-B3(-/-) mice resemble those recently reported for mice lacking the EphA4 receptor, which binds ephrin-B3 as well as other ephrins, suggesting that the binding of EphA4-bearing axonal processes to ephrin-B3 at the midline provides the repulsive signal that prevents corticospinal tract projections from recrossing the midline in the developing spinal cord.
  •  
47.
  • Köhler, Claudia, et al. (författare)
  • Auxin: a molecular trigger of seed development
  • 2018
  • Ingår i: Genes and Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 32, s. 479-490
  • Forskningsöversikt (refereegranskat)abstract
    • The evolution of seeds defines a remarkable landmark in the history of land plants. A developing seed contains three genetically distinct structures: the embryo, the nourishing tissue, and the seed coat. While fertilization is necessary to initiate seed development in most plant species, apomicts have evolved mechanisms allowing seed formation independently of fertilization. Despite their socio-economical relevance, the molecular mechanisms driving seed development have only recently begun to be understood. Here we review the current knowledge on the role of the hormone auxin for the initial development of the three seed structures and as a trigger of fertilization-independent seed development.
  •  
48.
  • Lanz, Michael Charles, et al. (författare)
  • Separable roles for Mec1/ATR in genome maintenance, DNA replication, and checkpoint signaling
  • 2018
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 32:11-12, s. 822-835
  • Tidskriftsartikel (refereegranskat)abstract
    • The Mec1/ATR kinase coordinates multiple cellular responses to replication stress. In addition to its canonical role in activating the checkpoint kinase Rad53, Mec1 also plays checkpoint-independent roles in genome maintenance that are not well understood. Here we used a combined genetic-phosphoproteomic approach to manipulate Mec1 activation and globally monitor Mec1 signaling, allowing us to delineate distinct checkpoint-independent modes of Mec1 action. Using cells in which endogenous Mec1 activators were genetically ablated, we found that expression of "free" Mec1 activation domains (MADs) can robustly activate Mec1 and rescue the severe DNA replication and growth defects of these cells back to wild-type levels. However, unlike the activation mediated by endogenous activator proteins, "free" MADs are unable to stimulate Mec1-mediated suppression of gross chromosomal rearrangements (GCRs), revealing that Mec1's role in genome maintenance is separable from a previously unappreciated proreplicative function. Both Mec1's functions in promoting replication and suppressing GCRs are independent of the downstream checkpoint kinases. Additionally, Mec1-dependent GCR suppression seems to require localized Mec1 action at DNA lesions, which correlates with the phosphorylation of activator-proximal substrates involved in homologous recombination-mediated DNA repair. These findings establish that Mec1 initiates checkpoint signaling, promotes DNA replication, and maintains genetic stability through distinct modes of action.
  •  
49.
  • Lindblom, Per, 1974, et al. (författare)
  • Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall.
  • 2003
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 17:15, s. 1835-40
  • Tidskriftsartikel (refereegranskat)abstract
    • Several platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) family members display C-terminal protein motifs that confer retention of the secreted factors within the pericellular space. To address the role of PDGF-B retention in vivo, we deleted the retention motif by gene targeting in mice. This resulted in defective investment of pericytes in the microvessel wall and delayed formation of the renal glomerulus mesangium. Long-term effects of lack of PDGF-B retention included severe retinal deterioration, glomerulosclerosis, and proteinuria. We conclude that retention of PDGF-B in microvessels is essential for proper recruitment and organization of pericytes and for renal and retinal function in adult mice.
  •  
50.
  • Liu, Yanjie, et al. (författare)
  • The conserved plant sterility gene HAP2 functions after attachment of fusogenic membranes in Chlamydomonas and Plasmodium gametes
  • 2008
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory Press (CSHL). - 0890-9369 .- 1549-5477. ; 22:8, s. 1051-1068
  • Tidskriftsartikel (refereegranskat)abstract
    • The cellular and molecular mechanisms that underlie species-specific membrane fusion between male and female gametes remain largely unknown. Here, by use of gene discovery methods in the green alga Chlamydomonas, gene disruption in the rodent malaria parasite Plasmodium berghei, and distinctive features of fertilization in both organisms, we report discovery of a mechanism that accounts for a conserved protein required for gamete fusion. A screen for fusion mutants in Chlamydomonas identified a homolog of HAP2, an Arabidopsis sterility gene. Moreover, HAP2 disruption in Plasmodium blocked fertilization and thereby mosquito transmission of malaria. HAP2 localizes at the fusion site of Chlamydomonas minus gametes, yet Chlamydomonas minus and Plasmodium hap2 male gametes retain the ability, using other, species-limited proteins, to form tight prefusion membrane attachments with their respective gamete partners. Membrane dye experiments show that HAP2 is essential for membrane merger. Thus, in two distantly related eukaryotes, species-limited proteins govern access to a conserved protein essential for membrane fusion.
  •  
Skapa referenser, mejla, bekava och länka
  • Resultat 1-50 av 109
Typ av publikation
tidskriftsartikel (104)
forskningsöversikt (5)
Typ av innehåll
refereegranskat (106)
övrigt vetenskapligt/konstnärligt (3)
Författare/redaktör
Mäkinen, Taija (4)
Alitalo, Kari (4)
Perlmann, T (3)
Hoog, C (3)
Sigvardsson, Mikael (3)
Nyström, Thomas, 196 ... (3)
visa fler...
Ericson, J (3)
Wagner, Gerhart E. H ... (3)
Ohlsson, Rolf (3)
Schlisio, S (3)
Köhler, Claudia (3)
Sun, X. (2)
Yuan, L. (2)
Johansson, Erik (2)
Aspenström, Pontus (2)
Betsholtz, C (2)
Heuchel, Rainer (2)
Chang, C (2)
Holmberg, J (2)
Ellis, E (2)
Abramsson, Alexandra ... (2)
Landegren, Ulf (2)
Betsholtz, Christer, ... (2)
Gerhardt, Holger, 19 ... (2)
Billker, Oliver (2)
Thorén, Lina (2)
Jacobsen, Sten Eirik ... (2)
Ljung, Karin (2)
Poellinger, L (2)
Heldin, Carl-Henrik (2)
Kanduri, Chandrasekh ... (2)
Visa, N (2)
Moustakas, Aristidis (2)
Somasundaram, Rajesh (2)
Sabouri, Nasim (2)
Kenchappa, RS (2)
Cantù, Claudio (2)
Theilgaard-Moench, K ... (2)
Muhr, J (2)
Figueiredo, Duarte (2)
Santos-González, Jua ... (2)
Samakovlis, Christos (2)
Bergsland, M (2)
Sjölinder, Mikael (2)
Mattsson, Anita (2)
Eichmann, Anne (2)
Briscoe, J (2)
Valenta, Tomas (2)
Hausmann, George (2)
Basler, Konrad (2)
visa färre...
Lärosäte
Karolinska Institutet (48)
Uppsala universitet (24)
Umeå universitet (15)
Göteborgs universitet (10)
Lunds universitet (10)
Linköpings universitet (9)
visa fler...
Sveriges Lantbruksuniversitet (5)
Stockholms universitet (3)
Södertörns högskola (2)
Kungliga Tekniska Högskolan (1)
Högskolan i Halmstad (1)
Örebro universitet (1)
visa färre...
Språk
Engelska (107)
Odefinierat språk (2)
Forskningsämne (UKÄ/SCB)
Naturvetenskap (28)
Medicin och hälsovetenskap (23)

År

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy