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61.
MOTIVATION: Searching a protein sequence database for homologs is a
powerful tool for discovering the structure and function of a sequence. Two
new methods for searching sequence databases have recently been described:
Probabilistic Smith-Waterman (PSW), which is based on Hidden Markov models
for a single sequence using a standard scoring matrix, and a new version of
BLAST (WU-BLAST2), which uses Sum statistics for gapped alignments.
RESULTS: This paper compares and contrasts the effectiveness of these
methods with three older methods (Smith- Waterman: SSEARCH, FASTA and
BLASTP). The analysis indicates that the new methods are useful, and often
offer improved accuracy. These tools are compared using a curated (by Bill
Pearson) version of the annotated portion of PIR 39. Three different
statistical criteria are utilized: equivalence number, minimum errors and
the receiver operating characteristic. For complete-length protein query
sequences from large families, PSW's accuracy is superior to that of the
other methods, but its accuracy is poor when used with partial-length query
sequences. False negatives are twice as common as false positives
irrespective of the search methods if a family-specific threshold score
that minimizes the total number of errors (i.e. the most favorable
threshold score possible) is used. Thus, sensitivity, not selectivity, is
the major problem. Among the analyzed methods using default parameters, the
best accuracy was obtained from SSEARCH and PSW for complete-length
proteins, and the two BLAST programs, plus SSEARCH, for partial-length
proteins.
相似文献
62.
Watanabe M Fiji HD Guo L Chan L Kinderman SS Slamon DJ Kwon O Tamanoi F 《The Journal of biological chemistry》2008,283(15):9571-9579
Protein geranylgeranylation is critical for the function of a number of proteins such as RhoA, Rac, and Rab. Protein geranylgeranyltransferase I (GGTase-I) and Rab geranylgeranyltransferase (RabGGTase) catalyze these modifications. In this work, we first describe the identification and characterization of small molecule inhibitors of GGTase-I (GGTI) with two novel scaffolds from a library consisting of allenoate-derived compounds. These compounds exhibit specific inhibition of GGTase-I and act by competing with a substrate protein. Derivatization of a carboxylic acid emanating from the core ring of one of the GGTI compounds dramatically improves their cellular activity. The improved GGTI compounds inhibit proliferation of a variety of human cancer cell lines and cause G(1) cell cycle arrest and induction of p21(CIP1/WAF1). We also report the identification of novel small molecule inhibitors of RabGGTase. These compounds were identified first by screening our GGTI compounds for those that also exhibited RabGGTase inhibition. This led to the discovery of a common structural feature for RabGGTase inhibitors: the presence of a characteristic six-atom aliphatic tail attached to the penta-substituted pyrrolidine core. Further screening led to the identification of compounds with preferential inhibition of RabGGTase. These compounds inhibit RabGGTase activity by competing with the substrate protein. These novel compounds may provide valuable reagents to study protein geranylgeranylation. 相似文献
63.
Carlson A Berkowitz JM Browning D Slamon DJ Gasson JC Yates KE 《DNA and cell biology》2005,24(5):311-316
The cellular fes gene encodes a 93-kilodalton protein-tyrosine kinase (p93) that is expressed in both normal and neoplastic myeloid cells. Increased c-Fes expression is associated with differentiation in normal myeloid cells and cell lines. Our hypothesis was that primary leukemia cells would show a similar pattern of increased expression in more differentiated cells. Therefore, we compared c-Fes expression in cells with an undifferentiated, blast phenotype (acute myelogenous leukemia--AML) to cells with a differentiated phenotype (chronic myelogenous leukemia--CML). Instead of differences in p93 expression levels, we found complex patterns of c-Fes immunoreactive proteins that corresponded with differentiation in normal and leukemic myeloid cells. The "blast" pattern consisted of c-Fes immunoreactive proteins p93, p74, and p70; the "differentiated" pattern showed two additional c-Fes immunoreactive proteins, p67 and p62. Using mRNA from mouse and human cell lines, we found deletion of one or more exons in the c-fes mRNA. Those deletions predicted truncation of conserved domains (CDC15/FCH and SH2) involved in protein-protein interactions. No deletions were found, however, within the kinase domain. We infer that alternative splicing generates a family of c-Fes proteins. This may be a mechanism to direct the c-Fes kinase domain to different subcellular locations and/or substrates at specific stages of myeloid cell differentiation. 相似文献
64.
Tyrosine phosphorylation has emerged as a mechanism to control cellular events in the nucleus. The c-Fes protein-tyrosine kinase is an important regulator of cell growth and differentiation in several cell types, and is found in the nucleus of hematopoietic cells. In this study, we showed nuclear localization of c-Fes in both hematopoietic (K562, TF-1, HEL, U937, and HL-60) and nonhematopoietic cell lines (293T, CaOv3, TfxH, MG-63, HeLa, DU-145) by immunofluorescence and confocal microscopy. c-Fes showed striking changes in subcellular localization at specific stages of mitosis. In interphase cells, the intranuclear distribution of c-Fes was diffuse with occasional bright foci. Some c-Fes was present in the cytosol after breakdown of the nuclear membrane, in prometaphase. At prometaphase and metaphase c-Fes was also associated with the chromosomes, in a punctate pattern that partially overlapped with the centromere. Further comparison with proteins that are known components of the kinetochore suggested that some c-Fes protein was located at the centromeric alpha-satellite DNA, between the kinetochores. At anaphase and telophase, c-Fes was entirely cytoplasmic and no protein was found associated with the chromosomes. The timing of c-Fes' appearance at the centromere coincides with the period of kinetochore assembly. These data suggest that c-Fes is recruited to the kinetochore during mitosis. 相似文献
65.
The effects of pretreatment with the antioxidants reduced glutathione (GSH), ascorbate (ASC), Trolox (TROL), and combined ascorbate and Trolox (ASC/TROL) exposure on the acute (24 h) toxicities (EC50 value) of the antidepressants amitriptyline, imipramine (tricyclic antidepressants), fluoxetine (a selective serotonin reuptake inhibitor; SSRI), and tranylcypromine (a monoamine oxidase inhibitor; MAOI) were determined in the rat (C6) glioma and human (1321N1) astrocytoma cell lines using the neutral red uptake assay. The effects of pretreatment with buthionine-[S, R]-sulfoximine (BSO), and manipulation of intracellular cyclic AMP (cAMP) using isoproterenol (beta-receptor agonist), 3-isobutyl-1-methylxanthine (IBMX; a phosphodiesterase inhibitor), and dibutyryl cyclic AMP (dBcAMP; cAMP analogue) on antidepressant toxicity were also determined. Protective responses were observed after antioxidant treatments and manipulation of cAMP in both C6 cells pretreated with dBcAMP (+dBcAMP) and 1321N1 cells not pretreated with dBcAMP (-dBcAMP), with a few exceptions in 1321N1 cells (-dBcAMP). Some protective responses occurred in C6 cells (-dBcAMP) and 1321N1 cells (+dBcAMP) after isoproterenol and combined IBMX/isoproterenol pretreatment but not after just IBMX pretreatment. Pretreatment with BSO enhanced toxicity with the exception of fluoxetine. The antidepressants caused increases in intracellular GSH in the C6 cells at subcytotoxic concentrations, with decreases in GSH occurring at higher concentrations. Cytotoxicity of the antidepressants may be partly mediated through oxidative stress with alterations in signal transduction pathways. 相似文献
66.
Motomi Ito Kuniaki Watanabe Yoko Kita Takayuki Kawahara DJ Crawford Tetsukazu Yahara 《Journal of plant research》2000,113(1):79-89
Eupatorium were examined by sequencing the internal transcribed spacers (ITS) of nuclear ribosomal DNA and restriction site analysis
of chloroplast DNA. Molecular data provided strong evidence that (1) this genus originated in North America, (2) the genus
diverged into three morphological species groups, Eutrochium, Traganthes and Uncasia in North America, and (3) one of the North American Uncasia lineages migrated into temperate Europe and eastern Asia over the Bering land bridge. The estimated divergence times support
a late Miocene to early Pliocene migration from North America to Eurasia via the Bering land bridge. A European species was
sister to all of the eastern Asian species examined. The disjunct distribution pattern of the genus Eupatorium is incongruent with the classical Arcto-Tertiary geoflora concept.
Received 13 September 1999/ Accepted in revised form 4 January 2000 相似文献
67.
Several studies have indicated that olfactory responses are impeded by
amiloride. Therefore, it was of interest to see whether, and if so which,
olfactory epithelial cellular compartments have amiloride- sensitive
structures. Using ultrastructural methods that involved rapid freezing,
freeze-substitution and low temperature embedding of olfactory epithelia,
this study shows that, in the rat, this tissue is immunoreactive to
antibodies against amiloride sensitive Na(+)- channels. However, microvilli
of olfactory supporting cells, as opposed to receptor cilia, contained most
of the immunoreactive sites. Apices from which the microvilli sprout and
receptor cell dendritic knobs had much less if any of the
amiloride-antibody binding sites. Using a direct ligand-binding
cytochemical method, this study also confirms earlier ones that showed that
olfactory receptor cell cilia have Na+, K(+)-ATPase. It is proposed that
supporting cell microvilli and the receptor cilia themselves have
mechanisms, different but likely complementary, that participate in
regulating the salt concentration around the receptor cell cilia. In this
way, both structures help to provide the ambient mucous environment for
receptor cells to function properly. This regulation of the salt
concentration of an ambient fluid environment is a function that the
olfactory epithelium shares with cells of transporting epithelia, such as
those of kidney.
相似文献
68.
Transgenic Research - 相似文献
69.
70.
Organ specific expression of ras oncoproteins during growth and development of the rat 总被引:5,自引:0,他引:5
Takeo Tanaka Noriaki Ida Hiroko Shimoda Chiaki Waki Dennis J. Slamon Martin J. Cline 《Molecular and cellular biochemistry》1986,70(1):97-104
Summary Expression of proteins encoded by the ras proto-oncogenes was examined in extracts from normal rat organs using anti-ras p21 antibodies generated against synthetic peptides. The highest level of ras p21 was found in brain (cerebrum) and was predominantly of c-Ha-ras origin. Levels of brain ras p21 did not vary from the newborn period of 3 months of age. Moderate levels of ras p21s were detected in lung, spleen and thymus. In contrast to the p21 in brain, these levels varied with the age of the rats and were encoded by other members of ras proto-oncogene family (Ki-ras or N-ras). This organ specific expression of different ras genes might be related to developmental control of gene expressions. 相似文献