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排序方式: 共有141条查询结果,搜索用时 15 毫秒
1.
Davide Danovi Amos Folarin Sabine Gogolok Christine Ender Ahmed M. O. Elbatsh P?r G. Engstr?m Stefan H. Stricker Sladjana Gagrica Ana Georgian Ding Yu Kin Pong U Kevin J. Harvey Patrizia Ferretti Patrick J. Paddison Jane E. Preston N. Joan Abbott Paul Bertone Austin Smith Steven M. Pollard 《PloS one》2013,8(10)
Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults and there are few effective treatments. GBMs contain cells with molecular and cellular characteristics of neural stem cells that drive tumour growth. Here we compare responses of human glioblastoma-derived neural stem (GNS) cells and genetically normal neural stem (NS) cells to a panel of 160 small molecule kinase inhibitors. We used live-cell imaging and high content image analysis tools and identified JNJ-10198409 (J101) as an agent that induces mitotic arrest at prometaphase in GNS cells but not NS cells. Antibody microarrays and kinase profiling suggested that J101 responses are triggered by suppression of the active phosphorylated form of polo-like kinase 1 (Plk1) (phospho T210), with resultant spindle defects and arrest at prometaphase. We found that potent and specific Plk1 inhibitors already in clinical development (BI 2536, BI 6727 and GSK 461364) phenocopied J101 and were selective against GNS cells. Using a porcine brain endothelial cell blood-brain barrier model we also observed that these compounds exhibited greater blood-brain barrier permeability in vitro than J101. Our analysis of mouse mutant NS cells (INK4a/ARF−/−, or p53−/−), as well as the acute genetic deletion of p53 from a conditional p53 floxed NS cell line, suggests that the sensitivity of GNS cells to BI 2536 or J101 may be explained by the lack of a p53-mediated compensatory pathway. Together these data indicate that GBM stem cells are acutely susceptible to proliferative disruption by Plk1 inhibitors and that such agents may have immediate therapeutic value. 相似文献
2.
Codon usage in the vertebrate hemoglobins and its implications 总被引:2,自引:0,他引:2
A study of codon usage in vertebrate hemoglobins revealed an evolutionary
trend toward elevated numbers of CpG codon boundary pairs in mammalian
hemoglobin alpha genes. Selection for CpG codon boundaries countering the
generally observed CpG suppression is strongly suggested by these data.
These observations parallel recently published experimental results that
indicate that constitutive expression of the human alpha-globin gene
appears to be determined by regulatory information encoded within the
structural gene. The possibility is raised that, in the absence of
selection, CpG decay can be used to date the evolutionary origin of a
mammalian alpha pseudogene from its active alpha gene.
相似文献
3.
Evolution of crystallins: expression of lens-specific proteins in the blind mammals mole (Talpa europaea) and mole rat (Spalax ehrenbergi) 总被引:3,自引:0,他引:3
Quax-Jeuken Y; Bruisten S; Bloemendal H; de Jong WW; Nevo E 《Molecular biology and evolution》1985,2(4):279-288
The mole (Talpa europaea; Insectivora) and the mole rat (Spalax ehrenbergi;
Rodentia) both have degenerated eyes as a convergent adaptation to
subterranean life. The rudimentary eye lenses of these blind mammals no
longer function in a visual process. The crystallin genes, which display a
lens-specific expression pattern, were studied in these blind mammals and
in related species with normal eyes by hybridizing their genomic DNAs with
probes obtained from cDNA clones for alpha A-, alpha B-, and beta
Bp-crystallins from calf and gamma 3- crystallin from the rat. For all
crystallin genes examined, the hybridization signals of mole and mole rat
genomic DNA were comparable, respectively, with those of shrew and of rat
and mouse, normal-vision representatives of the orders Insectivora and
Rodentia. The expression of the crystallins at the protein level was tested
by using antiserum specific for alpha-crystallin in immunofluorescence
reactions on lens sections of mole and mole rat eyes and by using antisera
against the beta- and gamma-crystallins on sections of the mole eye. All
antisera gave positive fluorescence reactions exclusively with lens tissue
of these blind mammals, indicating that the crystallins are still normally
expressed despite the fact that these lenses have had no function in a
visual process in these mammals for at least many million years. These
findings apparently imply that some unknown selective advantage has
conserved the crystallin genes and their expression after the loss of
normal function of the lenses.
相似文献
4.
5.
In Drosophila pseudoobscura, the amylase (Amy) multigene family is
contained within a series of inversions, or gene arrangements, on the third
chromosome. The Standard (ST), Santa Cruz (SC), and Tree Line (TL)
inversions are central to the phylogeny of arrangements, and have clusters
of other arrangements derived from them. The gene arrangements belonging to
each of these three clusters have a characteristic number of Amy genes,
ranging from three in ST to two in SC to one in TL. This distribution
pattern can reflect a history of either duplications or deletions, although
the data available in the past did not permit a decision between these
alternatives. We provide unambiguous evidence that three Amy genes were
present before the divergence of the ST, SC, and TL arrangements. Thus, the
current status of the Amy multigene family is the result of deletions in
the TL and SC arrangements, which created three new pseudogenes: TL
Amy2-psi, TL Amy3-psi, and SC Amy3- psi. Analysis of pseudogene sequences
revealed that, in the SC and ST arrangements, pseudogene evolution has been
retarded, most likely due to the homogenization effect of gene conversion.
Finally, by determining the original copy number, we have reconstructed the
evolutionary history of the Amy multigene family and linked it with the
evolution of the central gene arrangements.
相似文献
6.
7.
The alpha-amylase (Amy) multigene family in Drosophila pseudoobscura is
located on the third chromosome, which is polymorphic for more than 40
inverted gene arrangements. The number of copies in this family ranges from
one to three, depending on the arrangement in question. A previous study of
the three Amy genes from the Standard (ST) arrangement suggested either
that duplicated copies (Amy2 and Amy3) are functionally constrained or that
they are undergoing gene conversion with Amy1. In order to elucidate
further the pattern of molecular evolution in this family, we cloned and
sequenced four additional Amy genes, two from the Santa Cruz (SC) and two
from the Chiricahua (CH) gene arrangement. Of the two alternatives, only
the hypothesis of gene conversion is supported by the sequence analysis.
The homogenization effect of gene conversion has been strongest in SC,
whose copies differ by only two nucleotides, less noticeable in ST, and
negligible in the CH. Furthermore, the action of gene conversion is
apparently localized, occurring only in the coding region. Interestingly,
these results concur with the findings of other workers for the duplicated
Amy genes in the Drosophila melanogaster group. Thus, the occurrence of
gene conversion in the Amy multigene family seems to be a common feature in
the Drosophila species studied so far.
相似文献
8.
9.
The binding of [3H]flunitrazepam to benzodiazepine receptors in synaptic membranes and a digitonin-solubilized receptor fraction of rat brain is increased by avermectin B1a and gamma-aminobutyric acid (GABA). The effects of avermectin B1a and GABA are both sensitive to inhibition by (+)-bicuculline. Avermectin B1a and GABA both decrease the Kd and increase the Bmax of [3H]flunitrazepam binding to membranes. Kinetic analysis of the binding of [3H]flunitrazepam to rat brain membranes indicates that avermectin B1a and GABA reduce the rate constants of both association and dissociation between the ligand and the receptor. These results suggest a similar mechanism of modulation of benzodiazepine binding by avermectin B1a and GABA. This modulation may involve in interaction among the receptors for benzodiazepine, GABA and avermectin B1a. 相似文献
10.
Adenovirus-mediated p21((WAF1/SDII/CIP1)) gene transfer induces apoptosis of human cervical cancer cell lines 总被引:7,自引:0,他引:7
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p21((WAF1/SDII/CIP1)) (p21) arrests cell growth by inhibiting cyclin-depend kinases. To explore the potential of using p21 for the gene therapy of cervical cancer, we infected human papillomavirus (HPV)-positive cervical cancer cells (HeLa, SiHa, and Z172) and HPV-negative cervical cancer cells (C33A) with recombinant adenovirus encoding p21 cDNA. The results revealed that effective inhibition of cell growth could be achieved by sense p21 adenovirus but not antisense p21 adenovirus infection and occurred through apoptosis as measured by DNA fragmentation and chromatin condensation. Apoptosis was also observed in xenografts of human cervical cancer cells infected with sense p21 adenovirus, as confirmed by in situ terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL). The apoptosis was not prevented by overexpression of the bcl-2 transgene. To sum up, the apoptotic effect suggests that p21 should be a tumoricidal agent instead of a tumoristatic agent in preventing cervical cancers. In addition, our report substantiates the combination of the high efficiency of adenovirus vector-mediated gene delivery and the apoptotic effect of p21. 相似文献