Common polymorphisms in the promoter of the visfatin gene (PBEF1) influence plasma insulin levels in a French-Canadian population.

The adipokine visfatin (PBEF1) exhibits insulin-mimetic effects and correlates strongly with visceral adiposity. We sequenced visfatin gene exons and 1,480 bp of the promoter in 23 individuals, including 18 individuals from the Quebec Family Study (QFS) with varying degrees of abdominal visceral fat, assessed by computed tomography, and 5 individuals from the Saguenay-Lac-Saint-Jean region of Québec. We identified a synonymous polymorphism in exon 7 (SER301SER) but no nonsynonymous mutations. We observed an additional 10 polymorphisms, including 5 intronic, 4 within the promoter, and 1 within the 3' untranslated region. Further promoter sequencing (816 bp) identified five additional single nucleotide polymorphisms (SNPs) in the QFS population. To investigate the role of visfatin gene variants in obesity-related phenotypes, we genotyped a total of 13 SNPs in the promoter region of the gene. From these, we analyzed the seven common SNPs in the QFS sample (918 participants from 208 families). A significant association was found between two SNPs (rs9770242 and rs1319501), in perfect linkage disequilibrium, and fasting insulin levels (P = 0.002). These SNPs were also associated with fasting glucose (P

c-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade.

Cell transformation by growth-promoting oncoproteins renders cells extremely sensitive to apoptosis through an unknown mechanism affecting the mitochondrial pathway of apoptosis. We have shown previously that sensitization to apoptosis also correlated with the activation of the stress-activated protein kinase p38. In the present study, we investigated the role of p38 in c-Myc-dependent apoptosis induced by the anticancer agent cisplatin. Cisplatin treatment of Rat1 cells with deregulated expression of c-Myc resulted in nuclear fragmentation that was accompanied in all cells by the activation of Bax and the translocation of cytochrome c from the mitochondria to the cytoplasm. None of these features of apoptosis was induced in control Rat-1 cells. p38 was also activated by cisplatin only in cells with deregulated expression of c-Myc, but, in contrast with all features of apoptosis, this activation was not affected by Bcl-2. Remarkably, overexpression of an interfering mutant of the p38alpha isoform, but not p38beta, blocked cisplatin-induced Bax activation or cytochrome c release and nuclear fragmentation. Analysis of the kinase cascade upstream of p38 revealed a c-Myc-dependent activation by cisplatin of mitogen-activated protein kinase kinase (MKK) 3/6 and apoptosis signal-regulating kinase 1 (Ask1). Inhibition of Ask1 blocked p38 activation by cisplatin and all features of apoptosis. Several of these data were confirmed using other DNA-damaging agents. The findings indicated that c-Myc potentiation of the mitochondrial pathway of apoptosis results, at least in part, from a sensitization of Ask1 activation, allowing DNA-damaging agents to induce in cascade Ask1, p38alpha and Bax.