Kevin R. Webster

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In this study, we demonstrate that two important regulators of the cell cycle, cyclin-dependent kinase-4 and its inhibitor p16, are increased in the brains of cases of Alzheimer's disease patients compared with age-matched controls. Both proteins are increased in the pyramidal neurons of the hippocampus, including those neurons containing neurofibrillary(More)
Here we show that p53 protein is physically associated with tubulin in vivo and in vitro, and that it localizes to cellular microtubules. Treatment with vincristine or paclitaxel before DNA-damage or before leptomycin B treatment reduces nuclear accumulation of p53 and expression of mdm2 and p21. Overexpression of dynamitin or microinjection of anti-dynein(More)
N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive(More)
High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel(More)
Activation of CDK4 is regulated, in part, by its association with a D-type cyclin. Conversely, CDK4 activity is inhibited when it is bound to the cyclin-dependent kinase inhibitor, p16(INK4A). To investigate the molecular basis of the interactions between CDK4 and cyclin D1 or p16(INK4A) we performed site-directed mutagenesis of CDK4. The interaction was(More)
Flavopiridol analogues, thio- and oxoflavopiridols which contain a sulfur (16) or oxygen (18) atom linker between a chromone ring and the hydrophobic side chain, are selective cyclin-dependent kinase 1 (CDK1) inhibitors with an IC(50) of 110 and 130 nM. These analogues were prepared from key intermediate 7 by substituting the ethyl sulfoxide. Enantio pure(More)
Structure-activity studies of 1H-pyrazolo[3,4-b]pyridine 1 have resulted in the discovery of potent CDK1/CDK2 selective inhibitor 21h, BMS-265246 (CDK1/cycB IC(50)=6 nM, CDK2/cycE IC(50)=9 nM). The 2,6-difluorophenyl substitution was critical for potent inhibitory activity. A solid state structure of 21j, a close di-fluoro analogue, bound to CDK2 shows the(More)
Gene 32 protein (gp32), a single-stranded DNA-binding protein from bacteriophage T4, contains a zinc-binding subdomain with sequence homologies to the 3-cysteine/1-histidine zinc-binding motif found in a variety of retroviruses and plant viruses. In vitro studies suggest that autoregulation of gp32 occurs at the level of translation by gp32 specifically(More)
The bacteriophage T4 regA protein is a translational repressor of a group of T4 early mRNAs. We have characterized the binding of regA protein to polynucleotides and to specific RNAs. Binding to nucleic acids was monitored by the quenching of the intrinsic tryptophan fluorescence of regA protein. regA protein exhibited differential affinities for the(More)