Publications

Several lines of evidence suggest that tumor cells show elevated activity of the NF-kappaB transcription factor, a phenomenon often resulting from constitutive activity of IkappaB kinase beta (IKKbeta). However, others have found that loss of NF-kappaB activity or IKKbeta is tumor promoting. The role of NF-kappaB in tumor progression is therefore controversial and varies with tumor type. We sought to more extensively investigate the role IKKbeta in melanoma tumor development by specifically disrupting Ikkb in melanocytes in an established mouse model of spontaneous melanoma, whereby HRasV12 is expressed in a melanocyte-specific, doxycycline-inducible manner in mice null for the gene encoding the tumor suppressor inhibitor cyclin-dependent kinase 4/alternative reading frame (Ink4a/Arf). Our results show that Ink4a/Arf-/- mice with melanocyte-specific deletion of Ikkb were protected from HRasV12-initiated melanoma only when p53 was expressed. This protection was accompanied by cell cycle arrest, with reduced cyclin-dependent kinase 2 (Cdk2), Cdk4, Aurora kinase A, and Aurora kinase B expression. Increased p53-mediated apoptosis was also observed, with decreased expression of the antiapoptotic proteins Bcl2 and survivin. Enhanced stabilization of p53 involved increased phosphorylation at Ser15 and reduced phosphorylation of double minute 2 (Mdm2) at Ser166. Together, our findings provide genetic and mechanistic evidence that mutant HRas initiation of tumorigenesis requires Ikkbeta-mediated NF-kappaB activity.

The common view is that T-lymphocytes activate telomerase, a DNA polymerase that extends telomeres at chromosome ends, to delay senescence. We show that independently of telomerase, T cells elongate telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs). Upon contact with T cells, APCs degraded shelterin to donate telomeres, which were cleaved by TZAP, and then transferred in extracellular vesicles (EVs) at the immunological synapse. Telomere vesicles retained the Rad51 recombination factor that enabled them to fuse with T cell chromosomal ends causing an average lengthening of ∼3000 base pairs. Thus, we identify a previously unknown telomere transfer program that supports T cell lifespan.

Exposure of eukaryotic cells to extracellular stimuli results in activation of mitogen-activated protein kinase (MAPK) cascades composed of MAPKs, MAPK kinases (MAP2Ks), and MAPK kinase kinases (MAP3Ks). Mammals possess a large number of MAP3Ks, many of which can activate the c-Jun N-terminal kinase (JNK) MAPK cascade when overexpressed, but whose biological function is poorly understood. We examined the function of the MAP3K MEK kinase 1 (MEKK1) in proinflammatory signaling. Using MEKK1-deficient embryonic stem cells prepared by gene targeting, we find that, in addition to its function in JNK activation by growth factors, MEKK1 is required for JNK activation by diverse proinflammatory stimuli, including tumor necrosis factor alpha, IL-1, double-stranded RNA, and lipopolysaccharide. MEKK1 is also essential for induction of embryonic stem cell migration by serum factors, but is not required for activation of other MAPKs or the IkappaB kinase signaling cascade.

HomeCirculationVol. 106, No. 3AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update

No abstract is provided for this article.

One Ras-dependent protein kinase cascade leading from growth factor receptors to the ERK (extracellular signal-regulated kinases) subgroup of mitogen-activated protein kinases (MAPKs) is dependent on the protein kinase Raf-1, which activates the MEK (MAPK or ERK kinase) dual specificity kinases. A second protein kinase cascade leading to activation of the Jun kinases (JNKs) is dependent on MEKK (MEK kinase). A dual-specificity kinase that activates JNK, named JNKK, was identified that functions between MEKK and JNK. JNKK activated the JNKs but did not activate the ERKs and was unresponsive to Raf-1 in transfected HeLa cells. JNKK also activated another MAPK, p38 (Mpk2; the mammalian homolog of HOG1 from yeast), whose activity is regulated similarly to that of the JNKs.

Background This study investigated the comparability and reliability of computer- and paper-based measures of psychosocial constructs related to fruit and vegetable and dietary fat intake among adolescents. Methods An ethnically diverse sample of 76 adolescents was studied (mean age 13 years). Scales measured use of change strategies, self-efficacy, decisional balance, family influences, and peer influences separately for the two dietary outcomes. Results Comparability analyses indicated that responses for each of the 12 diet-related scales were not significantly different between the computer- and paper-based surveys. Internal consistencies were generally high (α from .61 to .97) with slightly better reliability on the computer- vs paper-based surveys. Test–retest reliabilities were adequate to good for most multiple-item scales (interclass correlation coefficients from .43 to .85 and .48 to .90 for paper and computer formats, respectively). Conclusions Computer- and paper-based measures of psychosocial constructs are appropriate and ready for use in either format for studies of dietary behaviors in young people.

The purpose of this study was twofold: first, to examine the effects of specific cut-off scoring points on the estimated prevalence of meeting health-related guidelines for physical activity in youth and, second, to document the differences in gender physical activity patterns according to two different cut-off points. The sample for the present study comprised 157 children (boys n= 64 and girls n= 93), aged 8 to 16 years old. Based on activities’ intensity (MET), the daily time spent in moderate-to-vigorous physical activity (MVPA) was calculated using an equation regression developed for adults. In addition, based on the same procedures (MET)data were analysed using the cut-off points (ranging between 614 counts. min- 1 at 6 years old to 1880 counts. min-1 for 16 years old) specially developed for children. The data analysis from youth’s cut-off points reveal that both sexes engaged in significantly ( p= 0.01) more MVPA when compared with cut-off points designed for adults. Boys engaged in significantly ( p= 0.01) more MVPA activities than girls regardless of the CSA cut-off point used. Our data also showed that, except for boys aged 14–16 years old, the percentage of students that reach the physical activity health-related criteria (at least 60 minutes of MVPA/day) was significantly higher in both boys (77.3% vs 93.9%; p< 0.05) andgirls (50% vs 79.3%; p< 0.01) when the youth’s cut-off point was used. The youth-specific cut-off points used could be an important improvement in studies that develop prescription guidelines for children and adolescents. This still needs to be refined, and as a result healthrelated criteria for young people need to be based on further research evidence.