👤 Victoria Hutter

Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepancies in understanding the complex role of PPARβ/δ in disease, having both anti- and pro-effects on inflammation. After ligand activation, PPARβ/δ regulates genes by two different mechanisms; induction and transrepression, the effects of which are difficult to differentiate directly. We studied the PPARβ/δ-regulation of lipopolysaccharide (LPS) induced inflammation (indicated by release of nitrite and IL-6) of rat pulmonary artery, using different combinations of agonists (GW0742 or L-165402) and antagonists (GSK3787 or GSK0660). LPS induced release of NO and IL-6 is not significantly reduced by incubation with PPARβ/δ ligands (either agonist or antagonist), however, co-incubation with an agonist and antagonist significantly reduces LPS-induced nitrite production and Show less

Height is a complex trait under strong genetic influence. To date, numerous genetic loci have been associated with height in individuals of European ancestry. However, few large-scale discovery genome-wide association studies (GWAS) of height in minority populations have been conducted and thus information about population-specific height regulation is limited. We conducted a GWA analysis of height in 8149 African-American (AA) women from the Women's Health Initiative. Genetic variants with P< 5 × 10(-5) (n = 169) were followed up in a replication data set (n = 20 809) and meta-analyzed in a total of 28 958 AAs and African-descent individuals. Twelve single-nucleotide polymorphisms (SNPs) representing 7 independent loci were significantly associated with height at P < 5 × 10(-8). We identified novel SNPs in 17q23 (TMEM100/PCTP) and Xp22.3 (ARSE) reflecting population-specific regulation of height in AAs and replicated five loci previously reported in European-descent populations [4p15/LCORL, 11q13/SERPINH1, 12q14/HMGA2, 17q23/MAP3K3 (mitogen-activated protein kinase3) and 18q21/DYM]. In addition, we performed an admixture mapping analysis of height which is both complementary and supportive to the GWA analysis and suggests potential associations between ancestry and height on chromosomes 4 (4q21), 15 (15q26) and 17 (17q23). Our findings provide insight into the genetic architecture of height and support the investigation of non-European-descent populations for identifying genetic factors associated with complex traits. Specifically, we identify new loci that may reflect population-specific regulation of height and report several known height loci that are important in determining height in African-descent populations. Show less

Despite the understanding of the importance of mitogen-activated protein (MAP) kinase activation in the stimulation of growth, little is known about the role of MAP kinase regulation during contact inhibited growth control. To investigate the role of the MAP kinase extracellular signal-regulated kinase (ERK) during the transition to a contact inhibited state, cultures of normal fibroblasts (BJ) were grown to different stages of confluency. The levels of MAP kinase phosphatase (MKP) expression and the amount of active ERK and MAP ERK kinase (MEK) in these cultures were assessed through western blot analysis and were compared to fibrosarcoma cell cultures (HT-1080), which lack contact inhibition. In normal fibroblasts, the amounts of active MEK and ERK decline at contact inhibition, concurrently with a rise in MKP-1, MKP-2, and MKP-3 protein levels. In contrast, fibrosarcoma cells appear to lack density-dependent regulation of the ERK pathway. Additionally, altering the redox environment of fibrosarcoma cells to a less reducing state, as seen during contact inhibition, results in increased MKP-1 expression. Taken together, these results suggest that the altered redox environment upon contact inhibition may contribute to the regulation of ERK inactivation by MKPs. Show less