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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
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Biologic and molecular characterization of two newly isolated ras-containing murine leukemia viruses. 总被引:7,自引:3,他引:4
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T N Fredrickson R R O''''Neill R A Rutledge T S Theodore M A Martin S K Ruscetti J B Austin J W Hartley 《Journal of virology》1987,61(7):2109-2119
A murine sarcoma virus (MSV) was recovered from an (NFS X NS.C58v-1) F1 mouse which developed splenic sarcoma and erythroleukemia 6 months after inoculation with a mink cell focus-inducing murine leukemia virus (MuLV) isolated from an NFS mouse infected with a wild mouse ecotropic MuLV. The MSV, designated NS.C58 MSV-1, induced foci of transformation in mouse and rat fibroblasts, and inoculation of mice of various strains 2 weeks of age or younger resulted in erythroleukemia and sarcomatous lesions in spleen, lymph node, and brain. The MSV provirus was molecularly cloned from a genomic library prepared from transformed non-producer rat cells. The 8.8-kilobase proviral DNA contained a 1.0-kilobase p21 ras coding segment which replaced most of the gp70-encoding portion of an MuLV, most likely the endogenous C58v-1 ecotropic virus. The ras oncogene is closely related to v-Ha-ras by hybridization, expression of p21 protein, and nucleotide sequence. It is nearly identical in sequence to v-bas, the only previously described transduced, activated mouse c-ras. At position 12 in the p21 coding region, arginine is substituted for the naturally occurring glycine present in c-ras. A second MSV isolate is described which is similar to NS.C58 MSV-1 except for a 100- to 200-base-pair deletion in the noncoding region of the ras-containing insert. 相似文献
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We determined the effects of acute stretch on spontaneous and arginine vasotocin (AVT)-driven contractions of the Anolis carolinensis uterus in vitro. Whole uteri from reproductively inactive females (October) were placed in a bath of oxygenated 32 degrees C Anolis "Ringer's." Two initial tensions were utilized, 1.5 g or 15 g, the latter being an estimate of the tension on the wall of a uterine compartment. Uteri were then exposed to either saline or AVT (50 ng/ml), and spontaneous or AVT-driven contractions were recorded for 20 min with the use of a strain gauge and physiograph. A similar experiment was performed on uteri from reproductively active females in the summer (June). Our results indicate that the effects of acute stretch and AVT on uterine contractility were qualitatively similar in summer and fall. That is, AVT induced a tonic contraction; stretch decreased the duration of the tonic contraction; the saline-treated uteri exhibited spontaneous rhythmic contractions; AVT increased the amplitude of the rhythmic contractions, but only at the lower tension; there were no effects of AVT on the timing (contraction interval, duration, rest interval) of the rhythmic contractions; and stretch increased the frequency of the rhythmic contractions. Season greatly influenced the magnitude of these contractile phenomena. Uteri tested during the breeding season exhibited greater distensibility, an increase in the amplitude and duration of the AVT-driven tonic contraction, and an increase in the frequency of both spontaneous and AVT-driven rhythmic contractions because of a decrease in both contraction duration and rest interval.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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Ultraviolet resonance Raman (UVRR) spectra, with 260-nm excitation, are reported for oxidized and reduced nicotinamide adenine dinucleotides (NAD+ and NADH, respectively). Corresponding spectra are reported for these coenzymes when bound to the enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and liver and yeast alcohol dehydrogenases (LADH and YADH). The observed differences between the coenzyme spectra are interpreted in terms of conformation, hydrogen bonding, and general environment polarity differences between bound and free coenzymes and between coenzymes bound to different enzymes. The possibility of adenine protonation is discussed. UVRR spectra with 220-nm excitation also are reported for holo- and apo-GAPDH (GAPDH-NAD+ and GAPDH alone, respectively). In contrast with the 260-nm spectra, these show only bands due to vibrations of aromatic amino acid residues of the protein. The binding of coenzyme to GAPDH has no significant effect on the aromatic amino acid bands observed. This result is discussed in the light of the known structural change of GAPDH on binding coenzyme. Finally, UVRR spectra with 240-nm excitation are reported for GAPDH and an enzyme-substrate intermediate of GAPDH. Perturbations are reported for tyrosine and tryptophan bands on forming the acyl enzyme. 相似文献