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Biomedical subjects

K R Lawson

Publications and source records attributed to K R Lawson.

10 recordsLinked to original sources
PubMed2006

Expression of inappropriate cadherins by epithelial tumor cells promotes endocytosis and degradation of E-cadherin via competition for p120(ctn).

Cadherin cell-cell adhesion proteins play an important role in modulating the behavior of tumor cells. E-cadherin serves as a suppressor of tumor cell invasion, and when tumor cells turn on the expression of a non-epithelial cadherin, they often express less E-cadherin, enhancing the tumorigenic phenotype of the cells. Here, we show that when A431 cells are forced to express R-cadherin, they dramatically downregulate the expression of endogenous E- and P-cadherin. In addition, we show that this downregulation is owing to increased turnover of the endogenous cadherins via clathrin-dependent endocytosis. p120(ctn) binds to the juxtamembrane domain of classical cadherins and has been proposed to regulate cadherin adhesive activity. One way p120(ctn) may accomplish this is to serve as a rheostat to regulate the levels of cadherin. Here, we show that the degradation of E-cadherin in response to expression of R-cadherin is owing to competition for p120(ctn).

Binding, Competitive↗
PubMed2001

A supramolecular system for quantifying aromatic stacking interactions.

A supramolecular complex for investigating the thermodynamic properties of intermolecular aromatic stacking interactions has been developed. The conformation of the complex is locked in a single well-defined conformation by an array of H-bonding interactions that force two aromatic rings on one end of the complex into a stacked geometry. Chemical double-mutant cycles have been used to measure an anthracene-aniline interaction (+0.6 +/- 0.8 kJ mol(-1)) and a pentafluorophenyl-aniline interaction (-0.4 +/- 0.9 kJ mol(-1)) in this system. Although the interactions are very weak, the pentafluorophenyl interaction is attractive, whereas the anthracene interaction is repulsive: this is consistent with the dominance of pi-electron electrostatic interactions. The nitropyrrole subunits used to control the conformation of these complexes lead to problems of aggregation and multiple conformational equilibria. The implications for the thermodynamic analysis are examined in detail, and the double-mutant-cycle approach is found to be remarkably robust with respect to such effects, since systematic errors in individual experiments are removed in a pair-wise fashion when the cycle is constructed.

Journal Article↗
PubMed2000

Sulindac sulfone inhibits K-ras-dependent cyclooxygenase-2 expression in human colon cancer cells.

Both the sulfide and sulfone metabolites of sulindac, a nonsteroidal anti-inflammatory drug, display anticarcinogenic effects in experimental models. Sulindac sulfide inhibits cyclooxygenase (COX) enzyme activities and has been reported to suppress ras-dependent signaling. However, the mechanisms by which sulindac sulfone suppresses cancer growth are not as defined. We studied the effects of these sulindac metabolites in human colon cancer-derived Caco-2 cells that have been transfected with an activated K-ras oncogene. Stable transfected clones expressed high levels of COX-2 mRNA and protein, compared with parental cells. K-ras-transfected cells formed tumors more quickly when injected into severe combined immunodeficiency disease mice than parental cells, and this tumorigenesis was suppressed by treatment with sulindac. Sulindac sulfone inhibited COX-2 protein expression, which resulted in a decrease in prostaglandin synthase E2 production. Sulindac sulfide had little effect on COX-2 in this model, but did suppress prostaglandin synthase E2 production, presumably by inhibiting COX enzyme activity. These data indicate that the sulfide and sulfone derivatives of sulindac exert COX-dependent effects by distinct mechanisms.

Animals↗
PubMed2000

Influence of K-ras activation on the survival responses of Caco-2 cells to the chemopreventive agents sulindac and difluoromethylornithine.

The nonsteroidal anti-inflammatory drug sulindac and the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) are both potent inhibitors of colon carcinogenesis in experimental models of this disease. The combination of these two agents is undergoing evaluation as a strategy for colon cancer chemoprevention in humans with resected colon polyps. We evaluated the effects of the major sulfide and sulfone metabolites of sulindac and DFMO alone, or in combinations, on the growth and survival of Caco-2 colon cancer-derived cells and in clones of these cells transfected with an activated K-ras oncogene. Both the sulfide and sulfone metabolites of sulindac reduced cell viability, measured by colony-forming assays, primarily by inducing apoptosis. Expression of an activated K-ras oncogene caused cells treated with either sulindac sulfide or sulfone to undergo apoptosis earlier than nontransfected controls. However, clonogenic survival, measured 2 weeks after drug treatment, was the same in both Caco-2 and ras-transfected Caco-2 cells treated with sulindac metabolites. A 24-h treatment with DFMO caused a dose-dependent decrease in the colony-forming ability of cells expressing an activated K-ras but had no effect on the viability of the parental Caco-2 cells. The DFMO-dependent decrease in colony formation in K-ras-activated cells occurred in the absence of apoptosis. Assessment of cell survival by colony-forming assays indicated that these two agents acted in an additive manner when combined. These data indicate that K-ras can influence the kinetics of apoptosis induction by sulindac metabolites and cell survival in response to DFMO. However, cytotoxicity induced by these agents occurs via unique mechanisms. These studies suggest that the combination of DFMO and sulindac may be useful in human cancer prevention strategies.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

2-Chloro-1-(2,4-dichlorophenyl)-3-(1H-imidazol-1-yl)-2-phenylpropan-1-one hydrochloride, a novel, nonmutagenic antibacterial with specific activity against anaerobic bacteria.

1-(2,4-Dichlorophenyl)-2-phenylpropen-1-one (2) is identified as a potent antibacterial agent. A compound, 2-chloro-1-(2,4-dichlorophenyl)-3-(1H-imidazol-1-yl)-2-phenylpropan++ +-1-one (5) has been designed with the intention of its acting as a pro-drug, liberating the lethal species 2 specifically within the target anaerobic bacterial cell following bioreduction by bacterial ferredoxin or related electron transfer proteins. The synthesis and biological activity of 5 is described and compared with the activities of the analogous alpha-bromo ketone 6 and alpha-fluoro ketone 7. Synthesis of 6, 7, and the corresponding alpha-hydroxy ketone 11 is also described.

Alkenes↗
PubMed1990

Long-term stability of individual differences in sustained attention in the early years.

The goal of this longitudinal study was to explore whether early measures of attention and inattention would be predictive of later attentiveness and whether there was any evidence of stable individual differences in attentiveness. Both full-term and preterm children were observed at 1, 2, and 3.5 years in free play and in more structured situations. For the group as a whole, and for full-terms separately, quantitative measures of inattention at 2 years were predictive of comparable measures at 3.5 years. For preterms separately, quantitative measures of inattention at 1 year were predictive of both behavior and the mothers' rating on the Conners Hyperactivity subscale at 3.5 years. Global, qualitative ratings of attentiveness at 1 and 2 years were predictive of mothers' ratings on the Conners at 3.5 years for the group as a whole and for full-terms separately. For full-terms only, the global ratings of attentiveness at 1 and 2 years were also predictive of 3.5-year quantitative measures of behavior. These data provide an encouraging base for further investigation of early individual differences in attentiveness and of possible early precursors of later attention deficits.

Attention↗
PubMed1990

The usefulness of reaction time tasks in studying attention and organization of behavior in young children.

Three studies explored reaction time procedures as a means of assessing sustained attention and response organization in preschoolers. In the first study, an auditory reaction time task was administered to 65 3.5-year-olds. Performance deteriorated over trials, paralleling results reported for older children and adults. Performance on the task was also related to the hyperactivity subscale of the Conners Parents' Questionnaire and to Stanford-Binet IQ. In a second cross-sectional study, performance on a visual reaction time task improved significantly from 2.5 to 4.5 years. A third study demonstrated individual stability and reasonable test-retest reliability for all measures. The results suggest that reaction time tasks can be usefully employed with young children to measure developmental changes and individual differences in sustained attention and organization of behavior.

Attention↗
PubMed1980

Intersensory function in newborns: effect of sound on visual preferences.

The results of this study indicate that newborn infants' fixation of a graduated series of visual stimuli comprised of a low (1), intermediate (4 or 16), and a high (64) number of cubes is significantly different in the absence and presence of sound (white-noise bursts). Relative to the no-sound condition, sound resulted in the infants' tendency to look more at the low-intensity visual stimulus and less at the high-intensity visual stimulus. These results provide support for the idea that the newborns' optimal or preferred amount of stimulation is based on the total amount or intensity of stimulus input, regardless of whether this is contributed to by stimulation from one or more than one modality.

Attention↗