'Sphingolipid activator proteins SAP-A, -B, -C and -D (also called saposins) are generated by proteolytic processing from a 73 kDa precursor and function as obligatory activators of lysosomal enzymes involved in glycosphingolipid metabolism. Although the SAP precursor can be recognized by the mannose-6-phosphate (M-6-P) receptor and shuttled directly from the ... More
A chimeric protein containing the N terminus of the adeno-associated virus rep protein recognizes its target site in an In vivo assay.
AuthorsCathomen T, Collete D, Weitzman MD
JournalJ Virol
PubMed ID10666268
'The Rep78 and Rep68 proteins of adeno-associated virus (AAV) type 2 are involved in DNA replication, regulation of gene expression, and targeting site-specific integration. They bind to a specific Rep recognition sequence (RRS) found in both the viral inverted terminal repeats and the AAVS1 integration locus on human chromosome 19. ... More
Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors.
Authors Lee He-Jin; Shin Soon Young; Choi Chan; Lee Young Han; Lee Seung-Jae;
JournalJ Biol Chem
PubMed ID11724769
'Mitochondrial dysfunction has been associated with Parkinson''s disease. However, the role of mitochondrial defects in the formation of Lewy bodies, a pathological hallmark of Parkinson''s disease has not been addressed directly. In this report, we investigated the effects of inhibitors of the mitochondrial electron-transport chain on the aggregation of alpha-synuclein, ... More
The 7472insC mitochondrial DNA mutation impairs the synthesis and extent of aminoacylation of tRNASer(UCN) but not its structure or rate of turnover.
Authors Toompuu Marina; Yasukawa Takehiro; Suzuki Tsutomu; Hakkinen Terhi; Spelbrink Johannes N; Watanabe Kimitsuna; Jacobs Howard T;
JournalJ Biol Chem
PubMed ID11919191
'The 7472insC mitochondrial DNA mutation in the tRNA(Ser(UCN)) gene is associated with sensorineural deafness combined, in some patients, with a wider neurological syndrome. In cultured cybrid cells it causes a 70% decrease in tRNA(Ser(UCN)) abundance and mild respiratory impairment, previously suggested to be due to decreased tRNA stability. When mitochondrial ... More
Evidence for a Functional Interaction between Cingulin and ZO-1 in Cultured Cells.
Authors D'Atri Fabio; Nadalutti Fabio; Citi Sandra;
JournalJ Biol Chem
PubMed ID12023291
'Cingulin, a protein component of the submembrane plaque of tight junctions (TJ), contains globular and coiled-coil domains and interacts in vitro with several TJ and cytoskeletal proteins, including the PDZ protein ZO-1. Overexpression of Xenopus cingulin in transfected Xenopus A6 cells resulted in the disruption of endogenous ZO-1 localization, suggesting ... More
Intestinal trefoil factor confers colonic epithelial resistance to apoptosis
AuthorsTaupin DR, Kinoshita K, Podolsky DK
JournalProc Natl Acad Sci U S A
PubMed ID10639160
'Intestinal trefoil factor (ITF) is an essential regulator of colonic epithelial restitution, the rapid migration of colonocytes over mucosal wounds. High levels of ITF are frequently present in colorectal cancers and derived cell lines. Mucosal restitution requires the detachment of epithelium from substrate, which would be expected to induce apoptosis. ... More
Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu.
'Overexpression of the transmembrane receptor tyrosine kinase ErbB2 is common in multiple malignancies, including breast and ovarian cancer. ErbB2 is resistant to degradation mediated by c-Cbl, the E3 ubiquitin ligase responsible for ligand-induced ubiquitination of ErbB1 (epidermal growth factor receptor). Because of its resistance to degradation, ErbB2 is the preferred ... More
The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E-BP1 at multiple sites.
Authors Herbert Terence P; Tee Andrew R; Proud Christopher G;
JournalJ Biol Chem
PubMed ID11799119
'The phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), a potent stimulator of Erk, leads to the phosphorylation of 4E-BP1 and its dissociation from eIF4E. In contrast to agonists such as insulin, this occurs independently of PKB activation. In this report, we investigate the mechanism by which TPA regulates 4E-BP1 phosphorylation. Treatment of ... More
Caspase 3 activity is required for skeletal muscle differentiation.
Authors Fernando Pasan; Kelly John F; Balazsi Kim; Slack Ruth S; Megeney Lynn A;
JournalProc Natl Acad Sci U S A
PubMed ID12177420
'The cellular alterations associated with skeletal muscle differentiation share a high degree of similarity with key phenotypic changes usually ascribed to apoptosis. For example, actin fiber disassembly/reorganization is a conserved feature of both apoptosis and differentiating myoblasts and the conserved muscle contractile protein, myosin light chain kinase, is required for ... More
PTEN associates with the vault particles in HeLa cells.
'PTEN is a tumor suppressor that primarily dephosphorylates phosphatidylinositol 3,4,5-trisphosphate to down-regulate the phosphoinositide 3-kinase/Akt signaling pathway. Although the cellular functions of PTEN as a tumor suppressor have been well characterized, the mechanism by which PTEN activity is modulated by other signal molecules in vivo remains poorly understood. In searching ... More
An N-terminal arginine-rich cluster and a proline-alanine-threonine repeat region determine the cellular localization of the herpes simplex virus type 1 ICP34.5 protein and its ligand, protein phosphatase 1.
Authors Mao Hanwen; Rosenthal Kenneth S;
JournalJ Biol Chem
PubMed ID11788604
'The ICP34.5 protein facilitates herpes simplex virus replication by binding and activating protein phosphatase 1 (PP1) by means of a very conserved C-terminal GADD34-like region. Natural variants of the ICP34.5 differing in the number of arginines in an Arg-rich cluster at the N terminus and the number of Pro-Ala-Thr repeats ... More
Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line.
'Nonsteroidal anti-inflammatory drugs, which inhibit cyclooxygenase (COX) activity, are powerful antineoplastic agents that exert their antiproliferative and proapoptotic effects on cancer cells by COX-dependent and/or COX-independent pathways. Celecoxib, a COX-2-specific inhibitor, has been shown to reduce the number of adenomatous colorectal polyps in patients with familial adenomatous polyposis. Here, we ... More
SKAP55 recruits to lipid rafts and positively mediates the MAPK pathway upon T cell receptor activation.
'T cell receptor (TCR) engagement triggers a series of events including protein tyrosine kinase activation, tyrosine phosphorylation of adapter proteins, and multiple protein-protein interactions. We observed that adapter protein SKAP55, the Src kinase-associated phosphoprotein, formed homodimers through its SH3 domain and SK region. SKAP55 as a substrate interacted with Fyn ... More
The NH2-terminal domain of Golgin-160 contains both Golgi and nuclear targeting information.
AuthorsHicks SW, Machamer CE.
JournalJ Biol Chem
PubMed ID12130652
Golgin-160 is a member of the golgin family of Golgi-localized membrane proteins. The COOH-terminal two-thirds of golgin-160 is predicted to form a coiled-coil, with an NH(2)-terminal ... More
I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD- 95-induced apoptosis.
AuthorsHu S, Vincenz C, Ni J, Gentz R, Dixit VM
JournalJ Biol Chem
PubMed ID9211860
The pivotal discovery that the death proteases caspase 8 (FLICE) and caspase 10 (Mch4/FLICE2) are recruited to the CD-95 and tumor necrosis factor receptor-1 signaling complexes suggested a mechanism used by these cytotoxic receptors to initiate apoptosis. In this report, we describe the cloning and characterization of I-FLICE, a novel ... More
An iron-regulated ferric reductase associated with the absorption of dietary iron.
AuthorsMcKie AT, Barrow D, Latunde-Dada GO, Rolfs A, Sager G, Mudaly E, Mudaly M, Richardson C, Barlow D, Bomford A, Peters TJ, Raja KB, Shirali S, Hediger MA, Farzaneh F, Simpson RJ.
JournalScience
PubMed ID11230685
The ability of intestinal mucosa to absorb dietary ferric iron is attributed to the presence of a brush-border membrane reductase activity that displays adaptive responses to iron status. We have isolated a complementary DNA, Dcytb (for duodenal cytochrome b), which encoded a putative plasma membrane di-heme protein in mouse duodenal ... More
Control of Actin Reorganization by Slingshot, a Family of Phosphatases that Dephosphorylate ADF/Cofilin.
The ADF (actin-depolymerizing factor)/cofilin family is a stimulus-responsive mediator of actin dynamics. In contrast to the mechanisms of inactivation of ADF/cofilin by kinases such as LIM-kinase 1 (LIMK1), much less is known about its reactivation through dephosphorylation. Here we report Slingshot (SSH), a family of phosphatases that have the property ... More
Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling.
How ligand binding alters integrin conformation in outside-in signaling, and how inside-out signals alter integrin affinity for ligand, have been mysterious. We address this with electron microscopy, physicochemical measurements, mutational introduction of disulfides, and ligand binding to alphaVbeta3 and alphaIIbbeta3 integrins. We show that a highly bent integrin conformation is ... More
Occludin 1B, a Variant of the Tight Junction Protein Occludin
AuthorsZoia Muresan,* David L. Paul, and Daniel A. Goodenough*
JournalMol Cell Biol
PubMed ID10679019
Occludin and claudin are the major integral membrane components of themammalian tight junction. Although more than 11 distinct claudins have beenidentified, only 1 occludin transcript has been reported thus far. Therefore, wesearched by reverse transcription-PCR for occludin-related sequences inMadin-Darby canine kidney (MDCK) mRNA and identified a transcript encodingan alternatively spliced ... More
Identification of the gene responsible for gelatinous drop-like corneal dystrophy.
AuthorsTsujikawa M, Kurahashi H, Tanaka T, Nishida K, Shimomura Y, Tano Y, Nakamura Y
JournalNature Genetics
PubMed ID10192395
Gelatinous drop-like corneal dystrophy (GDLD; OMIM 204870) is an autosomal recessive disorder characterized by severe corneal amyloidosis leading to blindness, with an incidence of 1 in 300,000 in Japan. Our previous genetic linkage study localized the gene responsible to a 2.6-cM interval on chromosome 1p. Clinical manifestations, which appear in ... More
The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate.
AuthorsMcCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP, Tufaro F
JournalNature Genetics
PubMed ID9620772
Hereditary multiple exostoses (HME) is an autosomal dominant disorder characterized by the formation of cartilage-capped tumours (exostoses) that develop from the growth plate of endochondral bone. This condition can lead to skeletal abnormalities, short stature and malignant transformation of exostoses to chondrosarcomas or osteosarcomas. Linkage analyses have identified three different ... More
Regulatory interaction of phosducin-like protein with the cytosolic chaperonin complex.
Authors McLaughlin Joseph N; Thulin Craig D; Hart Sarah J; Resing Katheryn A; Ahn Natalie G; Willardson Barry M;
JournalProc Natl Acad Sci U S A
PubMed ID12060742
Phosducin and phosducin-like protein (PhLP) bind G protein betagamma subunits and regulate their activity. This report describes a previously uncharacterized binding partner unique to PhLP that was discovered by coimmunoprecipitation coupled with mass spectrometric identification. Chaperonin containing tailless complex polypeptide 1 (CCT), a cytosolic chaperone responsible for the folding of ... More
Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity.
Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder resulting from the degeneration of motor neurons in the cerebral cortex, brainstem, and spinal cord. The cytopathological hallmark in the remaining motor neurons of ALS is the presence of ubiquitylated inclusions consisting of insoluble protein aggregates. In this paper we report ... More
A novel zinc-regulated human zinc transporter, hZTL1, is localized to the enterocyte apical membrane.
Zinc is essential to a wide range of cellular processes; therefore, it is important to elucidate the molecular mechanisms of zinc homeostasis. To date, no zinc transporters expressed at the enterocyte apical membrane, and so essential to mammalian zinc homeostasis, have been discovered. We identified hZTL1 as a human expressed ... More
PATZ attenuates the RNF4-mediated enhancement of androgen receptor-dependent transcription.
PATZ is a transcriptional repressor affecting the basal activity of different promoters, whereas RNF4 is a transcriptional activator. The association of PATZ with RNF4 switches the activation to repression of selected basal promoters. Because RNF4 interacts also with the androgen receptor (AR) functioning as a coactivator and, in turn, RNF4 ... More
Differential regulation of gene expression by PITX2 isoforms.
Authors Cox Carol J; Espinoza Herbert M; McWilliams Bryan; Chappell Kimberly; Morton Lisa; Hjalt Tord A; Semina Elena V; Amendt Brad A;
JournalJ Biol Chem
PubMed ID11948188
Three major PITX2 isoforms are differentially expressed in human, mice, zebrafish, chick, and frog tissues. To demonstrate differential regulation of gene expression by these isoforms we used three different promoters and three cell lines. Transient transfection of Chinese hamster ovary, HeLa, and LS-8 cell lines revealed differences in PITX2A and ... More
Glycogen Synthase Kinase-3 Couples AKT-dependent Signaling to the Regulation of p21Cip1 Degradation.
Authors Rossig Lothar; Badorff Cornel; Holzmann Yvonne; Zeiher Andreas M; Dimmeler Stefanie;
JournalJ Biol Chem
PubMed ID11779850
Signaling via the phosphoinositide 3-kinase (PI3K)/AKT pathway is crucial for the regulation of endothelial cell (EC) proliferation and survival, which involves the AKT-dependent phosphorylation of the DNA repair protein p21(Cip1) at Thr-145. Because p21(Cip1) is a short-lived protein with a high proteasomal degradation rate, we investigated the regulation of p21(Cip1) ... More
Participation of two members of the very long-chain acyl-CoA synthetase family in bile acid synthesis and recycling.
Authors Mihalik Stephanie J; Steinberg Steven J; Pei Zhengtong; Park Joseph; Kim Do G; Heinzer Ann K; Dacremont Georges; Wanders Ronald J A; Cuebas Dean A; Smith Kirby D; Watkins Paul A;
JournalJ Biol Chem
PubMed ID11980911
Bile acids are synthesized de novo in the liver from cholesterol and conjugated to glycine or taurine via a complex series of reactions involving multiple organelles. Bile acids secreted into the small intestine are efficiently reabsorbed and reutilized. Activation by thioesterification to CoA is required at two points in bile ... More
Oversulfated chondroitin/dermatan sulfates containing GlcAbeta1/IdoAalpha1-3GalNAc(4,6-O-disulfate) interact with L- and P-selectin and chemokines.
We previously reported that versican, a large chondroitin/dermatan sulfate (CS/DS) proteoglycan, interacts through its CS/DS chains with adhesion molecules L- and P-selectin and CD44, as well as chemokines. Here, we have characterized these interactions further. Using a metabolic inhibitor of sulfation, sodium chlorate, we show that the interactions of the ... More
Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis.
DNA hypomethylation on pericentromeric satellite regions is an early and frequent event associated with heterochromatin instability during human hepatocarcinogenesis. A DNA methyltransferase, DNMT3b, is required for methylation on pericentromeric satellite regions during mouse development. To clarify the molecular mechanism underlying DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis, we ... More
Involvement of DNase gamma in apoptosis associated with myogenic differentiation of C2C12 cells.
AuthorsShiokawa D, Kobayashi T, Tanuma S.
JournalJ Biol Chem
PubMed ID12050166
Nucleosomal DNA fragmentation is detected in myoblasts only when apoptosis is induced under differentiating conditions. However, the molecular mechanisms and the DNase responsible for the differentiation-dependent apoptotic DNA laddering are poorly understood. Here we show that a Ca(2+)/Mg(2+)-dependent endonuclease, DNase gamma, is induced in C2C12 myoblasts during myogenic differentiation and ... More