The keratin-binding protein Albatross regulates polarization of epithelial cells.
AuthorsSugimoto M, Inoko A, Shiromizu T, Nakayama M, Zou P, Yonemura S, Hayashi Y, Izawa I, Sasoh M, Uji Y, Kaibuchi K, Kiyono T, Inagaki M,
JournalJ Cell Biol
PubMed ID18838552
'The keratin intermediate filament network is abundant in epithelial cells, but its function in the establishment and maintenance of cell polarity is unclear. Here, we show that Albatross complexes with Par3 to regulate formation of the apical junctional complex (AJC) and maintain lateral membrane identity. In nonpolarized epithelial cells, Albatross ... More
Anti-apoptotic effect of the basic helix-loop-helix (bHLH) transcription factor DEC2 in human breast cancer cells.
AuthorsLiu Y, Sato F, Kawamoto T, Fujimoto K, Morohashi S, Akasaka H, Kondo J, Wu Y, Noshiro M, Kato Y, Kijima H,
JournalGenes Cells
PubMed ID20236182
'DEC1 (BHLHB2/Stra13/Sharp2) and DEC2 (BHLHB3/Sharp1) are basic helix-loop-helix (bHLH) transcription factors that are involved in circadian rhythms, differentiation and the responses to hypoxia. We examined whether DEC1 and DEC2 are involved in apoptosis regulation, in human breast cancer MCF-7 cells. We found that siRNA-mediated knockdown of DEC2 resulted in marked ... More
EPLIN mediates linkage of the cadherin catenin complex to F-actin and stabilizes the circumferential actin belt.
AuthorsAbe K, Takeichi M,
JournalProc Natl Acad Sci U S A
PubMed ID18093941
'The cadherin-catenin complex is the major machinery for cell-cell adhesion in many animal species. This complex in general associates with actin fibers at its cytoplasmic side, organizing the adherens junction (AJ). In epithelial cells, the AJ encircles the cells near their apical surface and forms the "zonula adherens" or "adhesion ... More
MicroRNA regulation of cyclooxygenase-2 during embryo implantation.
'The implantation process is complex, requiring reciprocal interactions between implantation-competent blastocysts and the receptive uterus. Because microRNAs (miRNAs) have major roles in regulating gene expression, we speculated that they participate in directing the highly regulated spatiotemporally expressed genetic network during implantation. Here, we show that two miRNAs, mmu-miR-101a and mmu-miR-199a*, ... More
Neurotrophic Activity of Neudesin, a Novel Extracellular Heme-binding Protein, Is Dependent on the Binding of Heme to Its Cytochrome b5-like Heme/Steroid-binding Domain.
AuthorsKimura I, Nakayama Y, Yamauchi H, Konishi M, Miyake A, Mori M, Ohta M, Itoh N, Fujimoto M,
JournalJ Biol Chem
PubMed ID18056703
'Neudesin is a secreted protein with neurotrophic activity in neurons and undifferentiated neural cells. We report here that neudesin is an extracellular heme-binding protein and that its neurotrophic activity is dependent on the binding of heme to its cytochrome b(5)-like heme/steroid-binding domain. At first, we found that at least a ... More
Dual roles of myocardin-related transcription factors in epithelial mesenchymal transition via slug induction and actin remodeling.
AuthorsMorita T, Mayanagi T, Sobue K,
JournalJ Cell Biol
PubMed ID18056415
'Epithelial-mesenchymal transition (EMT) is a critical process occurring during embryonic development and in fibrosis and tumor progression. Dissociation of cell-cell contacts and remodeling of the actin cytoskeleton are major events of the EMT. Here, we show that myocardin-related transcription factors (MRTFs; also known as MAL and MKL) are critical mediators ... More
An auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance.
AuthorsLee OH, Jain AK, Papusha V, Jaiswal AK,
JournalJ Biol Chem
PubMed ID17925401
'INrf2:Nrf2 are sensors of chemical/radiation stress. Nrf2 dissociates from INrf2 in response to a stress and translocates in the nucleus. This leads to induction of a battery of antioxidant genes that protect cells. Nrf2 is then exported out and degraded. INrf2 functions as an adaptor of ubiquitin ligase for ubiquitination ... More
Cytohesins are cytoplasmic ErbB receptor activators.
AuthorsBill A, Schmitz A, Albertoni B, Song JN, Heukamp LC, Walrafen D, Thorwirth F, Verveer PJ, Zimmer S, Meffert L, Schreiber A, Chatterjee S, Thomas RK, Ullrich RT, Lang T, Famulok M,
JournalCell
PubMed ID20946980
'Signaling by ErbB receptors requires the activation of their cytoplasmic kinase domains, which is initiated by ligand binding to the receptor ectodomains. Cytoplasmic factors contributing to the activation are unknown. Here we identify members of the cytohesin protein family as such factors. Cytohesin inhibition decreased ErbB receptor autophosphorylation and signaling, ... More
Elevated mitochondrial reactive oxygen species generation affects the immune response via hypoxia-inducible factor-1alpha in long-lived Mclk1+/- mouse mutants.
AuthorsWang D, Malo D, Hekimi S,
JournalJ Immunol
PubMed ID20007531
'Mitochondrial reactive oxygen species (ROS) are believed to stabilize hypoxia-inducible factor (HIF)-1alpha, a transcriptional regulator of the immune response. Mclk1 encodes a mitochondrial protein that is necessary for ubiquinone biosynthesis. Heterozygote Mclk1(+/-) mutant mice are long-lived despite increased mitochondrial ROS and decreased energy metabolism. In this study, Mclk1(+/-) mutant mice ... More
The spectrin cytoskeleton influences the surface expression and activation of human transient receptor potential channel 4 channels.
AuthorsOdell AF, Van Helden DF, Scott JL,
JournalJ Biol Chem
PubMed ID18048348
'Despite over a decade of research, only recently have the mechanisms governing transient receptor potential channel (TRPC) channel function begun to emerge, with an essential role for accessory proteins in this process. We previously identified a tyrosine phosphorylation event as critical in the plasma membrane translocation and activation of hTRPC4 ... More
Migration of culture-expanded human mesenchymal stem cells through bone marrow endothelium is regulated by matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3.
AuthorsDe Becker A, Van Hummelen P, Bakkus M, Vande Broek I, De Wever J, De Waele M, Van Riet I,
JournalHaematologica
PubMed ID17488654
'BACKGROUND AND OBJECTIVES: Mesenchymal stem cells (MSC) are adult stem cells that can be expanded many fold in vitro and have the therapeutic potential to restore the bone marrow microenvironment and support hematopoietic recovery after myeloablative conditioning for hematopoietic stem cell transplantation. Successful homing to the target tissue, such as ... More
Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi.
'BRAF and NRAS are common targets for somatic mutations in benign and malignant neoplasms that arise from melanocytes situated in epithelial structures, and lead to constitutive activation of the mitogen-activated protein (MAP) kinase pathway. However, BRAF and NRAS mutations are absent in a number of other melanocytic neoplasms in which ... More
Role of cdk2 in the sequential phosphorylation/activation of C/EBPbeta during adipocyte differentiation.
AuthorsLi X, Kim JW, Grønborg M, Urlaub H, Lane MD, Tang QQ,
JournalProc Natl Acad Sci U S A
PubMed ID17601773
'Upon induction of differentiation, growth-arrested (G(1) phase) 3T3-L1 preadipocytes express CCAAT/enhancer binding protein-beta (C/EBPbeta), initiating a transcriptional cascade. C/EBPbeta immediately undergoes a priming phosphorylation (on Thr(188)) by MAPK/ERK. However, the acquisition of DNA binding and transactivation capacity of C/EBPbeta is delayed until further phosphorylation (on Ser(184) or Thr(179)) by GSK3beta ... More
Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks.
AuthorsGalanty Y, Belotserkovskaya R, Coates J, Polo S, Miller KM, Jackson SP,
JournalNature
PubMed ID20016603
'DNA double-strand breaks (DSBs) are highly cytotoxic lesions that are generated by ionizing radiation and various DNA-damaging chemicals. Following DSB formation, cells activate the DNA-damage response (DDR) protein kinases ATM, ATR and DNA-PK (also known as PRKDC). These then trigger histone H2AX (also known as H2AFX) phosphorylation and the accumulation ... More
Ars2 links the nuclear cap-binding complex to RNA interference and cell proliferation.
AuthorsGruber JJ, Zatechka DS, Sabin LR, Yong J, Lum JJ, Kong M, Zong WX, Zhang Z, Lau CK, Rawlings J, Cherry S, Ihle JN, Dreyfuss G, Thompson CB,
JournalCell
PubMed ID19632182
'Here we identify a component of the nuclear RNA cap-binding complex (CBC), Ars2, that is important for miRNA biogenesis and critical for cell proliferation. Unlike other components of the CBC, Ars2 expression is linked to the proliferative state of the cell. Deletion of Ars2 is developmentally lethal, and deletion in ... More
Resistance to therapy caused by intragenic deletion in BRCA2.
AuthorsEdwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, Boyd J, Reis-Filho JS, Ashworth A,
JournalNature
PubMed ID18264088
'Cells with loss of BRCA2 function are defective in homologous recombination (HR) and are highly sensitive to inhibitors of poly(ADP-ribose) polymerase (PARP), which provides the basis for a new therapeutic approach. Here we show that resistance to PARP inhibition can be acquired by deletion of a mutation in BRCA2. We ... More
MKKS Is a Centrosome-shuttling Protein Degraded by Disease-causing Mutations via CHIP-mediated Ubiquitination.
AuthorsHirayama S, Yamazaki Y, Kitamura A, Oda Y, Morito D, Okawa K, Kimura H, Cyr DM, Kubota H, Nagata K,
JournalMol Biol Cell
PubMed ID18094050
'McKusick-Kaufman syndrome (MKKS) is a recessively inherited human genetic disease characterized by several developmental anomalies. Mutations in the MKKS gene also cause Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder with pleiotropic symptoms. However, little is known about how MKKS mutations lead to disease. Here, we show that disease-causing mutants of ... More
A novel CpG-free vertebrate insulator silences the testis-specific SP-10 gene in somatic tissues: role for TDP-43 in insulator function.
AuthorsAbhyankar MM, Urekar C, Reddi PP,
JournalJ Biol Chem
PubMed ID17932037
'Regulation of cell type-specific gene transcription is central to cellular differentiation and development. During spermatogenesis, a number of testis-specific genes are expressed in a precise spatiotemporal order. How these genes remain silent in the somatic tissues is not well understood. Our previous studies using the round spermatid-specific mouse SP-10 gene, ... More
ATR pathway is the primary pathway for activating G2/M checkpoint induction after re-replication.
AuthorsLin JJ, Dutta A,
JournalJ Biol Chem
PubMed ID17716975
'DNA replication is tightly controlled to ensure accurate chromosome duplication and segregation in each cell cycle. Inactivation of Geminin, an inhibitor of origin licensing, leads to re-replication in human tumor cells within the same cell cycle and triggers a G(2)/M checkpoint. We find that the primary pathway to signal that ... More
Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.
AuthorsMinegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A, Karasuyama H,
JournalNature
PubMed ID17676033
'Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities. Although some cases of familial HIES with autosomal dominant or recessive inheritance have been ... More
Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles.
AuthorsDavis ME, Zuckerman JE, Choi CH, Seligson D, Tolcher A, Alabi CA, Yen Y, Heidel JD, Ribas A,
JournalNature
PubMed ID20305636
'Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, and the potential use of RNAi for human therapy has been demonstrated by the finding ... More
STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling.
AuthorsIshikawa H, Barber GN,
JournalNature
PubMed ID18724357
'The cellular innate immune system is essential for recognizing pathogen infection and for establishing effective host defence. But critical molecular determinants responsible for facilitating an appropriate immune response-following infection with DNA and RNA viruses, for example-remain to be identified. Here we report the identification, following expression cloning, of a molecule ... More
ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks.
'DNA double-strand breaks (DSBs) initiate extensive local and global alterations in chromatin structure, many of which depend on the ATM kinase. Histone H2A ubiquitylation (uH2A) on chromatin surrounding DSBs is one example, thought to be important for recruitment of repair proteins. uH2A is also implicated in transcriptional repression; an intriguing ... More
Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP.
AuthorsHafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P, Rothballer A, Ascano M, Jungkamp AC, Munschauer M, Ulrich A, Wardle GS, Dewell S, Zavolan M, Tuschl T,
JournalCell
PubMed ID20371350
'RNA transcripts are subject to posttranscriptional gene regulation involving hundreds of RNA-binding proteins (RBPs) and microRNA-containing ribonucleoprotein complexes (miRNPs) expressed in a cell-type dependent fashion. We developed a cell-based crosslinking approach to determine at high resolution and transcriptome-wide the binding sites of cellular RBPs and miRNPs. The crosslinked sites are ... More
Post-transcriptional regulation of human pregnane X receptor by microRNA affects the expression of cytochrome P450 3A4.
AuthorsTakagi S, Nakajima M, Mohri T, Yokoi T,
JournalJ Biol Chem
PubMed ID18268015
'Pregnane X receptor (PXR) is a major transcription factor regulating the inducible expression of a variety of transporters and drug-metabolizing enzymes including cytochrome P450 (CYP) 3A4. We first found that the PXR mRNA level was not correlated with the PXR protein level in a panel of 25 human livers, indicating ... More
Structural basis of the 9-fold symmetry of centrioles.
AuthorsKitagawa D, Vakonakis I, Olieric N, Hilbert M, Keller D, Olieric V, Bortfeld M, Erat MC, Flückiger I, Gönczy P, Steinmetz MO,
JournalCell
PubMed ID21277013
'The centriole, and the related basal body, is an ancient organelle characterized by a universal 9-fold radial symmetry and is critical for generating cilia, flagella, and centrosomes. The mechanisms directing centriole formation are incompletely understood and represent a fundamental open question in biology. Here, we demonstrate that the centriolar protein ... More
Nucleosome-interacting proteins regulated by DNA and histone methylation.
AuthorsBartke T, Vermeulen M, Xhemalce B, Robson SC, Mann M, Kouzarides T,
JournalCell
PubMed ID21029866
Modifications on histones or on DNA recruit proteins that regulate chromatin function. Here, we use nucleosomes methylated on DNA and on histone H3 in an affinity assay, in conjunction with a SILAC-based proteomic analysis, to identify ... More
Treslin collaborates with TopBP1 in triggering the initiation of DNA replication.
AuthorsKumagai A, Shevchenko A, Shevchenko A, Dunphy WG,
JournalCell
PubMed ID20116089
TopBP1 has important roles in both DNA replication and checkpoint regulation in vertebrates. We have identified a protein called Treslin that associates with TopBP1 in Xenopus egg extracts. Depletion of Treslin from egg extracts strongly inhibits chromosomal DNA replication. Binding of Treslin to chromatin in egg extracts occurs independently of ... More
Diminished GATA4 protein levels contribute to hyperglycemia-induced cardiomyocyte injury.
AuthorsKobayashi S, Mao K, Zheng H, Wang X, Patterson C, O'Connell TD, Liang Q,
JournalJ Biol Chem
PubMed ID17525155
Hyperglycemia is an independent risk factor for diabetic heart failure. However, the mechanisms that mediate hyperglycemia-induced cardiac damage remain poorly understood. The transcription factor GATA4 is essential for cardiac homeostasis, and its protein levels are dramatically reduced in the heart in response to diverse pathologic stresses. In this study, we ... More
The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia.
AuthorsJin H, White SR, Shida T, Schulz S, Aguiar M, Gygi SP, Bazan JF, Nachury MV,
JournalCell
PubMed ID20603001
The BBSome is a complex of Bardet-Biedl Syndrome (BBS) proteins that shares common structural elements with COPI, COPII, and clathrin coats. Here, we show that the BBSome constitutes a coat complex that sorts membrane proteins to primary cilia. The BBSome is the major effector of the Arf-like GTPase Arl6/BBS3, and ... More
Mastermind-like Domain-containing 1 (MAMLD1 or CXorf6) Transactivates the Hes3 Promoter, Augments Testosterone Production, and Contains the SF1 Target Sequence.
AuthorsFukami M, Wada Y, Okada M, Kato F, Katsumata N, Baba T, Morohashi KI, Laporte J, Kitagawa M, Ogata T,
JournalJ Biol Chem
PubMed ID18162467
Although chromosome X open reading frame 6 (CXorf6) has been shown to be a causative gene for hypospadias, its molecular function remains unknown. To clarify this, we first examined CXorf6 protein structure, identifying homology to mastermind-like 2 (MAML2) protein, which functions as a co-activator in canonical Notch signaling. Transactivation analysis ... More
Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1.
AuthorsHossain Z, Ali SM, Ko HL, Xu J, Ng CP, Guo K, Qi Z, Ponniah S, Hong W, Hunziker W,
JournalProc Natl Acad Sci U S A
PubMed ID17251353
Wwtr1 is a widely expressed 14-3-3-binding protein that regulates the activity of several transcription factors involved in development and disease. To elucidate the physiological role of Wwtr1, we generated Wwtr1-/- mice by homologous recombination. Surprisingly, although Wwtr1 is known to regulate the activity of Cbfa1, a transcription factor important for ... More
Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted.
AuthorsInoue Y, Tanaka N, Tanaka Y, Inoue S, Morita K, Zhuang M, Hattori T, Sugamura K,
JournalJ Virol
PubMed ID17522231
The penetration of various viruses into host cells is accomplished by hijacking the host endocytosis machinery. In the case of severe acute respiratory syndrome coronavirus (SARS-CoV) infection, viral entry is reported to require a low pH in intracytoplasmic vesicles; however, little is known about how SARS-CoV invades such compartments. Here ... More
Novel nuclear import of Vpr promoted by importin alpha is crucial for human immunodeficiency virus type 1 replication in macrophages.
AuthorsNitahara-Kasahara Y, Kamata M, Yamamoto T, Zhang X, Miyamoto Y, Muneta K, Iijima S, Yoneda Y, Tsunetsugu-Yokota Y, Aida Y,
JournalJ Virol
PubMed ID17344301
Monocytes/macrophages are major targets of human immunodeficiency virus type 1 (HIV-1) infection. The viral preintegration complex (PIC) of HIV-1 enters the nuclei of monocyte-derived macrophages, but very little PIC migrates into the nuclei of immature monocytes. Vpr, one of the accessory gene products of HIV-1, is essential for the nuclear ... More
Dengue virus (DV) replication in monocyte-derived macrophages is not affected by tumor necrosis factor alpha (TNF-alpha), and DV infection induces altered responsiveness to TNF-alpha stimulation.
AuthorsWati S, Li P, Burrell CJ, Carr JM,
JournalJ Virol
PubMed ID17626094
Tumor necrosis factor alpha (TNF-alpha) is believed to play a significant role in the pathogenesis of dengue virus (DV) infection, with elevated levels of TNF-alpha in the sera of DV-infected patients paralleling the severity of disease and TNF-alpha release being coincident with the peak of DV production from infected monocyte-derived ... More
AuthorsZhang X, Zhou K, Wang R, Cui J, Lipton SA, Liao FF, Xu H, Zhang YW,
JournalJ Biol Chem
PubMed ID17303576
The incidence of Alzheimer disease (AD) and vascular dementia is greatly increased following cerebral ischemia and stroke in which hypoxic conditions occur in affected brain areas. beta-Amyloid peptide (Abeta), which is derived from the beta-amyloid precursor protein (APP) by sequential proteolytic cleavages from beta-secretase (BACE1) and presenilin-1 (PS1)/gamma-secretase, is widely ... More
Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression.
AuthorsLinsley PS, Schelter J, Burchard J, Kibukawa M, Martin MM, Bartz SR, Johnson JM, Cummins JM, Raymond CK, Dai H, Chau N, Cleary M, Jackson AL, Carleton M, Lim L,
JournalMol Cell Biol
PubMed ID17242205
microRNAs (miRNAs) are abundant, approximately 21-nucleotide, noncoding regulatory RNAs. Each miRNA may regulate hundreds of mRNA targets, but the identities of these targets and the processes they regulate are poorly understood. Here we have explored the use of microarray profiling and functional screening to identify targets and biological processes triggered ... More
Cycloheximide protects HepG2 cells from serum withdrawal-induced apoptosis by decreasing p53 and phosphorylated p53 levels.
AuthorsBai J, Cederbaum AI,
JournalJ Pharmacol Exp Ther
PubMed ID16971506
Cycloheximide (CHX), an inhibitor of protein synthesis, has been reported to prevent cell death in a wide variety of cell types and produced by different apoptotic stimuli. However, the mechanisms by which CHX protects cells from apoptosis are still unclear. In this study, we investigated whether p53 plays a role ... More
RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins.
DNA double-strand breaks (DSBs) not only interrupt the genetic information, but also disrupt the chromatin structure, and both impairments require repair mechanisms to ensure genome integrity. We showed previously that RNF8-mediated chromatin ubiquitylation protects genome integrity by promoting the accumulation of repair factors at DSBs. Here, we provide evidence that, ... More
Calcium flickers steer cell migration.
AuthorsWei C, Wang X, Chen M, Ouyang K, Song LS, Cheng H,
JournalNature
PubMed ID19118385
Directional movement is a property common to all cell types during development and is critical to tissue remodelling and regeneration after damage. In migrating cells, calcium has a multifunctional role in directional sensing, cytoskeleton redistribution, traction force generation, and relocation of focal adhesions. Here we visualize high-calcium microdomains ('calcium flickers') ... More
FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination.
AuthorsDupont S, Mamidi A, Cordenonsi M, Montagner M, Zacchigna L, Adorno M, Martello G, Stinchfield MJ, Soligo S, Morsut L, Inui M, Moro S, Modena N, Argenton F, Newfeld SJ, Piccolo S,
JournalCell
PubMed ID19135894
The assembly of the Smad complex is critical for TGFbeta signaling, yet the mechanisms that inactivate or empower nuclear Smad complexes are less understood. By means of siRNA screen we identified FAM (USP9x), a deubiquitinase acting as essential and evolutionarily conserved component in TGFbeta and bone morphogenetic protein signaling. Smad4 ... More
Aberrant chromosome morphology in human cells defective for Holliday junction resolution.
AuthorsWechsler T, Newman S, West SC,
JournalNature
PubMed ID21399624
In somatic cells, Holliday junctions can be formed between sister chromatids during the recombinational repair of DNA breaks or after replication fork demise. A variety of processes act upon Holliday junctions to remove them from DNA, in events that are critical for proper chromosome segregation. In human cells, the BLM ... More
Imaging of Rab5 activity identifies essential regulators for phagosome maturation.
AuthorsKitano M, Nakaya M, Nakamura T, Nagata S, Matsuda M,
JournalNature
PubMed ID18385674
Efficient phagocytosis of apoptotic cells is crucial for tissue homeostasis and the immune response. Rab5 is known as a key regulator of the early endocytic pathway and we have recently shown that Rab5 is also implicated in apoptotic cell engulfment; however, the precise spatio-temporal dynamics of Rab5 activity remain unknown. ... More
From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus.
AuthorsMusunuru K, Strong A, Frank-Kamenetsky M, Lee NE, Ahfeldt T, Sachs KV, Li X, Li H, Kuperwasser N, Ruda VM, Pirruccello JP, Muchmore B, Prokunina-Olsson L, Hall JL, Schadt EE, Morales CR, Lund-Katz S, Phillips MC, Wong J, Cantley W, Racie T, Ejebe KG, Orho-Melander M, Melander O, Koteliansky V, Fitzgerald K, Krauss RM, Cowan CA, Kathiresan S, Rader DJ,
JournalNature
PubMed ID20686566
Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, ... More
A MicroRNA targeting dicer for metastasis control.
AuthorsMartello G, Rosato A, Ferrari F, Manfrin A, Cordenonsi M, Dupont S, Enzo E, Guzzardo V, Rondina M, Spruce T, Parenti AR, Daidone MG, Bicciato S, Piccolo S,
JournalCell
PubMed ID20603000
Although specific microRNAs (miRNAs) can be upregulated in cancer, global miRNA downregulation is a common trait of human malignancies. The mechanisms of this phenomenon and the advantages it affords remain poorly understood. Here we identify a microRNA family, miR-103/107, that attenuates miRNA biosynthesis by targeting Dicer, a key component of ... More
Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme.
AuthorsNakagawa K, Hirota Y, Sawada N, Yuge N, Watanabe M, Uchino Y, Okuda N, Shimomura Y, Suhara Y, Okano T,
JournalNature
PubMed ID20953171
Vitamin?K occurs in the natural world in several forms, including a plant form, phylloquinone (PK), and a bacterial form, menaquinones (MKs). In many species, including humans, PK is a minor constituent of hepatic vitamin?K content, with most hepatic vitamin?K content comprising long-chain MKs. Menaquinone-4 (MK-4) is ubiquitously present in extrahepatic ... More
Functional genomic screen for modulators of ciliogenesis and cilium length.
AuthorsKim J, Lee JE, Heynen-Genel S, Suyama E, Ono K, Lee K, Ideker T, Aza-Blanc P, Gleeson JG,
JournalNature
PubMed ID20393563
Primary cilia are evolutionarily conserved cellular organelles that organize diverse signalling pathways. Defects in the formation or function of primary cilia are associated with a spectrum of human diseases and developmental abnormalities. Genetic screens in model organisms have discovered core machineries of cilium assembly and maintenance. However, regulatory molecules that ... More
Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis.
AuthorsOberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, Hakem R, Salvesen GS, Green DR,
JournalNature
PubMed ID21368763
Caspase-8 has two opposing biological functions--it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development, T-lymphocyte activation, and resistance to necrosis induced by tumour necrosis factor-a (TNF-a) and related family ligands. Here we show that development ... More
Gp78 Cooperates with RMA1 in ER-associated Degradation of CFTR{Delta}F508.
AuthorsMorito D, Hirao K, Oda Y, Hosokawa N, Tokunaga F, Cyr DM, Tanaka K, Iwai K, Nagata K,
JournalMol Biol Cell
PubMed ID18216283
Monitoring Editor: Thomas Sommer Misfolded or improperly assembled proteins in the endoplasmic reticulum (ER) are exported into the cytosol and degraded via the ubiquitin-proteasome pathway, a process termed ER-associated degradation (ERAD). S. cerevisiae Hrd1p/Der3p is an ER membrane-spanning ubiquitin ligase that participates in ERAD of the cystic fibrosis transmembrane conductance ... More
RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins.
Accumulation of repair proteins on damaged chromosomes is required to restore genomic integrity. However, the mechanisms of protein retention at the most destructive chromosomal lesions, the DNA double-strand breaks (DSBs), are poorly understood. We show that RNF8, a RING-finger ubiquitin ligase, rapidly assembles at DSBs via interaction of its FHA ... More
Cohesin mediates transcriptional insulation by CCCTC-binding factor.
AuthorsWendt KS, Yoshida K, Itoh T, Bando M, Koch B, Schirghuber E, Tsutsumi S, Nagae G, Ishihara K, Mishiro T, Yahata K, Imamoto F, Aburatani H, Nakao M, Imamoto N, Maeshima K, Shirahige K, Peters JM,
JournalNature
PubMed ID18235444
Cohesin complexes mediate sister-chromatid cohesion in dividing cells but may also contribute to gene regulation in postmitotic cells. How cohesin regulates gene expression is not known. Here we describe cohesin-binding sites in the human genome and show that most of these are associated with the CCCTC-binding factor (CTCF), a zinc-finger ... More
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.
AuthorsIshikawa H, Ma Z, Barber GN,
JournalNature
PubMed ID19776740
The innate immune system is critical for the early detection of invading pathogens and for initiating cellular host defence countermeasures, which include the production of type I interferon (IFN). However, little is known about how the innate immune system is galvanized to respond to DNA-based microbes. Here we show that ... More
Force sensing by mechanical extension of the Src family kinase substrate p130Cas.
AuthorsSawada Y, Tamada M, Dubin-Thaler BJ, Cherniavskaya O, Sakai R, Tanaka S, Sheetz MP,
JournalCell
PubMed ID17129785
How physical force is sensed by cells and transduced into cellular signaling pathways is poorly understood. Previously, we showed that tyrosine phosphorylation of p130Cas (Cas) in a cytoskeletal complex is involved in force-dependent activation of the small GTPase Rap1. Here, we mechanically extended bacterially expressed Cas substrate domain protein (CasSD) ... More
Non-transcriptional control of DNA replication by c-Myc.
AuthorsDominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B, Li M, Galloway DA, Gu W, Gautier J, Dalla-Favera R,
JournalNature
PubMed ID17597761
The c-Myc proto-oncogene encodes a transcription factor that is essential for cell growth and proliferation and is broadly implicated in tumorigenesis. However, the biological functions required by c-Myc to induce oncogenesis remain elusive. Here we show that c-Myc has a direct role in the control of DNA replication. c-Myc interacts ... More
ZRP-1 controls Rho GTPase-mediated actin reorganization by localizing at cell-matrix and cell-cell adhesions.
AuthorsBai CY, Ohsugi M, Abe Y, Yamamoto T,
JournalJ Cell Sci
PubMed ID17652164
Focal adhesion protein ZRP-1/TRIP6 has been implicated in actin reorganization and cell motility. The role of ZRP-1, however, remained obscure because previously reported data are often conflicting one another. In the present study, we examined roles of ZRP-1 in HeLa cells. ZRP-1 is localized to the cell-cell contact sites as ... More
Microtubule plus-end-tracking proteins target gap junctions directly from the cell interior to adherens junctions.
AuthorsShaw RM, Fay AJ, Puthenveedu MA, von Zastrow M, Jan YN, Jan LY,
JournalCell
PubMed ID17289573
Gap junctions are intercellular channels that connect the cytoplasms of adjacent cells. For gap junctions to properly control organ formation and electrical synchronization in the heart and the brain, connexin-based hemichannels must be correctly targeted to cell-cell borders. While it is generally accepted that gap junctions form via lateral diffusion ... More
Low-density Lipoprotein Receptor-related Protein-1 (LRP1) Mediates Autophagy and Apoptosis Caused by Helicobacter pylori VacA.
AuthorsYahiro K, Satoh M, Nakano M, Hisatsune J, Isomoto H, Sap J, Suzuki H, Nomura F, Noda M, Moss J, Hirayama T,
JournalJ Biol Chem
PubMed ID22822085
In Helicobacter pylori infection, vacuolating cytotoxin (VacA)-induced mitochondrial damage leading to apoptosis is believed to be a major cause of cell death. It has also been proposed that VacA-induced autophagy serves as a host mechanism to limit toxin-induced cellular damage. Apoptosis and autophagy are two dynamic and opposing processes that ... More
Large T antigen promotes JC virus replication in G2-arrested cells by inducing ATM- and ATR-mediated G2 checkpoint signaling.
AuthorsOrba Y, Suzuki T, Makino Y, Kubota K, Tanaka S, Kimura T, Sawa H,
JournalJ Biol Chem
PubMed ID19903823
Large T antigen (TAg) of the human polyomavirus JC virus (JCV) possesses DNA binding and helicase activities, which, together with various cellular proteins, are required for replication of the viral genome. We now show that JCV-infected cells expressing TAg accumulate in the G(2) phase of the cell cycle as a ... More
Differential patterns of microRNA expression in neuroblastoma are correlated with prognosis, differentiation, and apoptosis.
AuthorsChen Y, Stallings RL,
JournalCancer Res
PubMed ID17283129
Neuroblastoma accounts for 15% of pediatric cancer deaths, and although a few protein-coding genes, such as MYCN, are involved with aggressive pathogenicity, the identification of novel biological targets for therapeutic intervention is still a necessary prerequisite for improving patient survival. Expression profiling of 157 microRNA (miRNA) loci in 35 primary ... More