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131.
Suppressive effect of topoisomerase inhibitors on JC polyomavirus propagation in human neuroblastoma cells
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Souichi Nukuzuma Kazuo Nakamichi Masanori Kameoka Shigeki Sugiura Chiyoko Nukuzuma Takafumi Tasaki Tsutomu Takegami 《Microbiology and immunology》2016,60(4):253-260
JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system, in immunocompromised patients. Because no drugs have been approved for treating PML, many antiviral agents are currently being investigated for this purpose. The inhibitory effects of the topoisomerase I inhibitors topotecan and β‐lapachone were assessed by investigating viral replication, propagation and viral protein 1 (VP1) production in cultured cells. JCPyV replication was assayed using the human neuroblastoma cell line IMR‐32 transfected with the JCPyV plasmid and RT‐ PCR combined with Dpn I treatment. Dpn I digests the input plasmid DNA containing methylated adenosine, but not newly replicated JCPyV DNA, in IMR‐32 cells. It was found that JCPyV replicates less in IMR‐32 cells treated with topotecan or β‐lapachone than in untreated cells. Moreover, drug treatment of JCI cells, which are IMR‐32 cells persistently infected with JCPyV, led to a reduction in the amount of JCPyV DNA and population of VP1‐positive cells. These results demonstrate that topotecan and β‐lapachone affects JCPyV propagation in human neuroblastoma cell lines, suggesting that topotecan and β‐lapachone could potentially be used to treat PML. 相似文献
132.
Goto K Nakanishi Y Ohkutsu S Ogawa K Tasaki M Ohta M Inohae S Tateyama S Kawabata T 《Theriogenology》1987,27(5):819-826
The relationship between plasma progesterone (P(4)) levels before and after superovulation treatment and embryo yield and quality was examined in Japanese Black cattle. It is concluded that a plasma P(4) level at the start of follicle stimulating hormone (FSH) injections is related to embryo quality. The P(4) level of over 3.0 ng/ml appears to be useful in preselection of donors when we want to get more than 8 normal (transferable) embryos on the average. 相似文献
133.
Y Aoyagi I Tasaki J Okumura T Muramatsu 《Comparative biochemistry and physiology. A, Comparative physiology》1988,91(4):765-768
1. Energy cost of whole-body protein synthesis was measured in vivo in chicks by comparing the changes in protein synthesis and heat production after the administration of cycloheximide, an inhibitor of protein synthesis. 2. Incorporation of phenylalanine into whole-body protein fraction was promptly inhibited after the intravenous injection of cycloheximide, and the effect was sustained for at least 3 hr. 3. Both whole-body protein synthesis and total heat production were significantly reduced by the cycloheximide administration. 4. The energy cost of whole-body protein synthesis was calculated to be 5.35 kJ per g protein synthesis, and hence on a molar basis 7.52 ATPs are required per peptide bond synthesis. 相似文献
134.
Effect of internal colchicine on asymmetrical displacement currents was studied by internally perfusing squid giant axons with a solution containing colchicine. It was found that (1) asymmetrical displacement currents were composed of two parts; colchicine-sensitive and colchicine-resistant; that (2) the colchicine-sensitive part had a definite rising phase while the colchicine-resistant one showed an instantaneous jump, followed by exponential decay; and that (3) the colchicine-sensitive part related to normal Na channels. 相似文献
135.
Yuki Mitaka Eisuke Tasaki Tomonari Nozaki Taro Fuchikawa Kazuya Kobayashi Kenji Matsuura 《Insect Science》2020,27(2):202-211
Eusocial insects display a caste system in which different castes are morpho-logically and physiologically specialized for different tasks.Recent studies have revealed that epigenetic modifications,including DNA methylation and histone modification,me-diate caste determination and differentiation,longevity,and polyethism in eusocial insects.Although there has been a growing interest in the relationship between epigenetic mech-anisms and phenotypic plasticity in termites,there is ltte information about differential expression levels among castes and expression sites for these genes in termites.Here we show royaltissuc-specific expression of epigenetic modification genes in the termite Reticulitermes speratus.Using RNA-seq,we identified 74 genes,including three DNA methyltransferases,seven sirtuins,48 Trithorax group proteins,and 16 Polycomb group proteins.Among these genes,15 showed king-specific expression,and 52 showed age-dependent differential expression in kings and queens.Quantitative real-time PCR revealed that DNA methyltransferase 3 is expressed specifically in the king's testis and fat body,whereas some histone modification genes are remarkably expressed in the king's testis and queen's ovary.These findings imply that epigenetic modification plays important roles in the gamete production process in termite kings and queens. 相似文献
136.
Single units were recorded through glass microelectrodes placed on the optic disk or on the retina of the opened eye of the frog (Rana catesbiana). Units were classified as A-, B-, and C-fibers according to conduction velocities. By the method of collision between naturally elicited and electrically elicited impulses, many of the B-fibers and some A- and C-fibers, which showed unusual behavior to photic stimulation, were found to be efferent fibers. Retinal effects of the efferent nerves were studied by repetitive stimulation and cooling of the optic nerve. The effects were found to be both inhibitory and excitatory. 相似文献
137.
S Urano S Fetzer R G Harvey K Tasaki P R LeBreton 《Biochemical and biophysical research communications》1988,154(2):789-795
The effects of 7-alkyl substitution on the reversible intercalation of the proximate carcinogen trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene (BAD) to calf thymus DNA have been examined using time-resolved fluorescence spectroscopy. The results indicate that in 10(-3) M sodium cacodylate the binding constant of BAD is 1.8 x 10(3) M-1. 7-Ethyl substitution decreases the binding constant 1.6 times, while 7-methyl substitution increases the binding constant 1.7 times. UV Photoelectron data and results from ab initio molecular orbital calculations suggest that an increase in polarizability contributes to the increased binding accompanying methyl substitution. The decreased binding accompanying ethyl substitution arises from steric inhibition. The physical binding data correlates with the decrease in carcinogenic activity which occurs with 7-ethyl substitution of benz[a]anthracene metabolites. 相似文献
138.
Takafumi Tasaki Adriana Zakrzewska Drew D. Dudgeon Yonghua Jiang John S. Lazo Yong Tae Kwon 《The Journal of biological chemistry》2009,284(3):1884-1895
The N-end rule pathway is a ubiquitin-dependent system where E3 ligases
called N-recognins, including UBR1 and UBR2, recognize type-1 (basic) and
type-2 (bulky hydrophobic) N-terminal residues as part of N-degrons. We have
recently reported an E3 family (termed UBR1 through UBR7) characterized by the
70-residue UBR box, among which UBR1, UBR2, UBR4, and UBR5 were captured
during affinity-based proteomics with synthetic degrons. Here we characterized
substrate binding specificity and recognition domains of UBR proteins.
Pull-down assays with recombinant UBR proteins suggest that 570-kDa UBR4 and
300-kDa UBR5 bind N-degron, whereas UBR3, UBR6, and UBR7 do not. Binding
assays with 24 UBR1 deletion mutants and 31 site-directed UBR1 mutations
narrow down the degron-binding activity to a 72-residue UBR box-only fragment
that recognizes type-1 but not type-2 residues. A surface plasmon resonance
assay shows that the UBR box binds to the type-1 substrate Arg-peptide with
Kd of ∼3.4 μm. Downstream from the UBR
box, we identify a second substrate recognition domain, termed the N-domain,
required for type-2 substrate recognition. The ∼80-residue N-domain shows
structural and functional similarity to 106-residue Escherichia coli
ClpS, a bacterial N-recognin. We propose a model where the 70-residue UBR box
functions as a common structural element essential for binding to all known
destabilizing N-terminal residues, whereas specific residues localized in the
UBR box (for type 1) or the N-domain (for type 2) provide substrate
selectivity through interaction with the side group of an N-terminal amino
acid. Our work provides new insights into substrate recognition in the N-end
rule pathway.The N-end rule pathway is a ubiquitin
(Ub)2-dependent
proteolytic system in which N-terminal residues of short-lived proteins
function as an essential component of degradation signals (degrons) called
N-degrons (Fig. 1A)
(1-15).
An N-degron can be created from a pre-N-degron through specific N-terminal
modifications (12).
Specifically, in mammals, N-terminal Asn and Gln are tertiary destabilizing
residues that function through their deamidation by N-terminal amidohydrolases
into the secondary destabilizing N-terminal residues Asp and Glu, respectively
(6,
16)
(Fig. 1A). N-terminal
Asp and Glu are secondary destabilizing residues that function through their
arginylation by ATE1 R-transferase, which creates the primary
destabilizing residue Arg at the N terminus
(4,
8)
(Fig. 1A). N-terminal
Cys can also function as a tertiary destabilizing residue through its
oxidation in a manner depending on nitric oxide and oxygen (O2);
the oxidized Cys residue is subsequently arginylated by ATE1
(8,
13,
17).Open in a separate windowFIGURE 1.A, the mammalian N-end rule pathway. N-terminal residues are
indicated by single-letter abbreviations for amino acids. Yellow
ovals denote the rest of a protein substrate. C*
denotes oxidized N-terminal Cys, either Cys-sulfinic acid
[CysO2(H)] or Cys-sulfonic acid [CysO3(H)]. The Cys
oxidation requires nitric oxide and oxygen (O2) or its derivatives.
The oxidized Cys is arginylated by ATE1 Arg-tRNA-protein transferase
(R-transferase). N-recognins also recognize internal (non-N-terminal)
degrons in other substrates of the N-end rule pathway. B, the
X-peptide pull-down assay. Left, a 12-mer peptide bearing N-terminal
Arg (type 1), Phe (type 2), Trp (type 2), or Gly (stabilizing control) residue
was cross-linked through its C-terminal Cys residue to Ultralink Iodoacetyl
beads. Right, the otherwise identical 12-mer peptide, bearing
C-terminal biotinylated Lys instead of Cys, was conjugated, via biotin, to the
streptavidin-Sepharose beads. C, the X-peptide pull-down assay of
endogenous UBR proteins using testes extracts. Extracts from mouse testes were
mixed with bead-conjugated X-peptides bearing N-terminal Phe (F), Gly
(G), or Arg (R). After centrifugation, captured proteins
were separated and subjected to anti-UBR immunoblotting. Mo, a
pull-down reaction with mock beads. D, the X-peptide pull-down assays
using rat testis extracts were performed in the presence of varying
concentrations of NaCl. After incubation and washing, bound proteins were
eluted by 10 mm Tyr-Ala for Phe-peptide, 10 mm Arg-Ala
for Arg-peptide, and 5 mm Tyr-Ala and 5 mm Arg-Ala for
Val-peptide. Eluted proteins were subjected to immunoblotting for UBR1 and
UBR5. E, cytoplasmic fractions of wild-type (+/+),
Ubr1-/-, Ubr2-/-,
Ubr1-/-Ubr2-/-, and
Ubr1-/-Ubr2-/-Ubr4RNAi
MEFs were subjected to X-peptide pull-down assay. Precipitated proteins were
separated and analyzed by immunoblotting for UBR1 and UBR4.N-terminal Arg together with other primary destabilizing N-terminal
residues are directly bound by specific E3 Ub ligases called N-recognins
(3,
7,
9). Destabilizing N-terminal
residues can be created through the removal of N-terminal Met or the
endoproteolytic cleavage of a protein, which exposes a new amino acid at the N
terminus (12,
13). N-terminal degradation
signals can be divided into type-1 (basic; Arg, Lys, and His) and type-2
(bulky hydrophobic; Phe, Leu, Trp, Tyr, and Ile) destabilizing residues
(2,
12). In addition to a
destabilizing N-terminal residue, a functional N-degron requires at least one
internal Lys residue (the site of a poly-Ub chain formation) and a
conformational feature required for optimal ubiquitylation
(1,
2,
18). UBR1 and UBR2 are
functionally overlapping N-recognins
(3,
7,
9). Our proteomic approach
using synthetic peptides bearing destabilizing N-terminal residues captured a
set of proteins (200-kDa UBR1, 200-kDa UBR2, 570-kDa UBR4, and 300-kDa
UBR5/EDD) characterized by a 70-residue zinc finger-like domain termed the UBR
box
(10-12).
UBR5 is a HECT E3 ligase known as EDD (E3 identified by
differential display)
(19) and a homolog of
Drosophila hyperplastic discs
(20). The mammalian genome
encodes at least seven UBR box-containing proteins, termed UBR1 through UBR7
(10). UBR box proteins are
generally heterogeneous in size and sequence but contain, with the exception
of UBR4, specific signatures unique to E3s or a substrate recognition subunit
of the E3 complex: the RING domain in UBR1, UBR2, and UBR3; the HECT domain in
UBR5; the F-box in UBR6 and the plant homeodomain domain in UBR7
(Fig. 2B). The
biochemical properties of more recently identified UBR box proteins, such as
UBR3 through UBR7, are largely unknown.Open in a separate windowFIGURE 2.The binding properties of the UBR box family members to type-1 and
type-2 destabilizing N-terminal residues. A, the X-peptide
pull-down assay with overexpressed, full-length UBR proteins: UBR2, UBR3 (in
S. cerevisiae cells), UBR4, UBR5 (in COS7 cells), and UBR6 and UBR7
(in the wheat germ lysates). Precipitates were analyzed by immunoblotting (for
UBR2, UBR3, UBR4, and UBR5) with tag-specific antibodies as indicated in
B or autoradiography (for UBR6 and UBR7). B, the structures
of UBR box proteins. Shown are locations of the UBR box, the N-domain, and
other E3-related domains. UBR, UBR box; RING, RING finger;
UAIN, UBR-specific autoinhibitory domain; CRD, cysteine-rich
domain; PHD, plant homeodomain; HECT, HECT domain.Studies using knock-out mice implicated the N-end rule pathway in cardiac
development and signaling, angiogenesis
(8,
15), meiosis
(9), DNA repair
(21), neurogenesis
(15), pancreatic functions
(22), learning and memory
(23,
24), female development
(9), muscle atrophy
(25), and olfaction
(11). Mutations in human
UBR1 is a cause of Johanson-Blizzard syndrome
(22), an autosomal recessive
disorder with multiple developmental abnormalities
(26). Other functions of the
pathway include: (i) a nitric oxide and oxygen (O2) sensor
controlling the proteolysis of RGS4, RGS5, and RGS16
(8,
13,
17), (ii) a heme sensor
through hemin-dependent inhibition of ATE1 function
(27), (iii) the regulation of
short peptide import through the peptide-modulated degradation of the
repressor of the import (28,
29), (iv) the control of
chromosome segregation through the degradation of a separate produced cohesin
fragment (30), (v) the
regulation of apoptosis through the degradation of a caspase-processed
inhibitor of apoptosis (31,
32), (vi) the control of the
human immunodeficiency virus replication cycle through the degradation of
human immunodeficiency virus integrase
(10,
33), and (vii) the regulation
of leaf senescence in plants
(34).In the present study we characterized substrate binding specificities and
recognition domains of UBR proteins. In our binding assays, UBR1, UBR2, UBR4,
and UBR5 were captured by N-terminal degradation determinants, whereas UBR3,
UBR6, and UBR7 were not. We also report that in contrast to other E3 systems
that usually recognize substrates through protein-protein interface, UBR1 and
UBR2 have a general substrate recognition domain termed the UBR box.
Remarkably, a 72-residue UBR box-only fragment fully retains its structural
integrity and thereby the ability to recognize type-1 N-end rule substrates.
We also report that the N-domain, structurally and functionally related with
bacterial N-recognins, is required for recognizing type-2 N-end rule
substrates. We discuss the evolutionary relationship between eukaryotic and
prokaryotic N-recognins. 相似文献
139.
Masayoshi Tasaki Mitsuharu Ueda Sho Ochiai Sho Murata Yu Su Satoru Shinriki Makoto Shono Yukio Ando 《Biochemical and biophysical research communications》2010,400(4):559-562
Recent studies clearly demonstrated that several types of pathogenic amyloid proteins acted as agents that could transmit amyloidosis by means of a prion-like mechanism. Systemic AA amyloidosis is one of the most severe complications of chronic inflammatory disorders, particularly rheumatoid arthritis. It is well known that, similar to an infectious prion protein, amyloid-enhancing factor (AEF) acts as a transmissible agent in AA amyloidosis. However, how AEF transmits AA amyloidosis in vivo remained to be fully elucidated. In the present study, we focused on finding cell-free forms of AEF and its carriers in circulation by using the murine transfer model of AA amyloidosis. We first determined that circulating cell-free AEF existed in blood and plasma in mice with systemic AA amyloidosis. Second, we established that plasma exosomes containing AA amyloid oligomers derived from serum amyloid A had AEF activity and could transmit systemic AA amyloidosis via a prion-like mechanism. These novel findings should provide insights into the transmission mechanism of systemic amyloidoses. 相似文献
140.
Furuya M Kirschbaum SB Paulovich A Pauli BU Zhang H Alexander JS Farr AG Ruddell A 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(10):5769-5777
The lymphatic circulation mediates drainage of fluid and cells from the periphery through lymph nodes, facilitating immune detection of lymph-borne foreign Ags. The 10.1.1 mAb recognizes a lymphatic endothelial Ag, in this study purified by Ab-affinity chromatography. SDS-PAGE and mass spectrometry identified murine chloride channel calcium-activated 1 (mCLCA1) as the 10.1.1 Ag, a 90-kDa cell-surface protein expressed in lymphatic endothelium and stromal cells of spleen and thymus. The 10.1.1 Ab-affinity chromatography also purified LFA-1, an integrin that mediates leukocyte adhesion to endothelium. This mCLCA1-LFA-1 interaction has functional consequences, as lymphocyte adhesion to lymphatic endothelium was blocked by 10.1.1 Ab bound to endotheliumor by LFA-1 Ab bound to lymphocytes. Lymphocyte adhesion was increased by cytokine treatment of lymphatic endothelium in association with increased expression of ICAM-1, an endothelial surface protein that is also a ligand for LFA-1. By contrast, mCLCA1 expression and the relative contribution of mCLCA1 to lymphocyte adhesion were unaffected by cytokine activation, demonstrating that mCLCA1 and ICAM-1 interactions with LFA-1 are differentially regulated. mCLCA1 also bound to the LFA-1-related Mac-1 integrin that is preferentially expressed on leukocytes. mCLCA1-mediated adhesion of Mac-1- or LFA-1-expressing leukocytes to lymphatic vessels and lymph node lymphatic sinuses provides a target for investigation of lymphatic involvement in leukocyte adhesion and trafficking during the immune response. 相似文献