Role of peroxisome proliferator-activated receptor-gamma coactivator-1alpha in the transcriptional regulation of the human uncoupling protein 2 gene in INS-1E cells.
ABSTRACT A role of uncoupling protein 2 (UCP2) as negative modulator of insulin secretion has been suggested, but the transcriptional pathways regulating beta-cell UCP2 gene expression have been established in rodents only. We show here that the underlying sequence motifs are not conserved in the human gene and provide evidence for regulatory mechanisms involving the transcriptional cofactor peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1alpha). PGC-1alpha potentiates thyroid hormone (T(3))-mediated transcriptional activation of the human UCP2 gene in INS-1E cells. Two thyroid hormone response elements (TREs) located at -322/-317 (TRE1) and -170/-165 (TRE2) were identified, and mutation of either TRE1 or TRE2 abrogated the stimulatory effect of T(3) treatment. Furthermore, two E-box motifs at -911/-906 (E1) and -743/-738 (E2) are involved in the regulation of UCP2 gene expression by sterol regulatory element binding protein isoforms (SREBP)-1a, -1c, and -2. Mutational analysis revealed that the presence of either E1 or E2 is sufficient to mediate activation of UCP2 gene transcription by nuclear active SREBPs. PGC-1alpha coactivates liver X receptor-mediated expression of SREBP-1c as well as dexamethasone-stimulated SREBP-2 expression in INS-1E cells. These transcriptional responses are antagonized by orphan nuclear receptor short heterodimer partner overexpression, which might explain its positive effects on glucose-stimulated insulin secretion in beta-cells overexpressing UCP2. We also provide evidence that despite a lack of sequence homology within the regulatory region, the principal mechanisms regulating UCP2 gene expression are similar in rats and humans, being consistent with a role for UCP2 as a modulator of insulin secretion in humans.
- SourceAvailable from: Tomo Yonezawa
Dataset: UCP2 review
- [Show abstract] [Hide abstract]
ABSTRACT: An ever-increasing number of studies highlight the role of uncoupling protein 2 (UCP2) in a broad range of physiological and pathological processes. The knowledge of the molecular mechanisms of UCP2 regulation is becoming fundamental in both the comprehension of UCP2-related physiological events and the identification of novel therapeutic strategies based on UCP2 modulation. The study of UCP2 regulation is a fast-moving field. Recently, several research groups have made a great effort to thoroughly understand the various molecular mechanisms at the basis of UCP2 regulation. In this review, we describe novel findings concerning events that can occur in a concerted manner at various levels: Ucp2 gene mutation (single nucleotide polymorphisms), UCP2 mRNA and protein expression (transcriptional, translational, and protein turn-over regulation), UCP2 proton conductance (ligands and post-transcriptional modifications), and nutritional and pharmacological regulation of UCP2.Cellular and Molecular Life Sciences CMLS 06/2013; · 5.62 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: In order to reside and multiply successfully within the host macrophages, Leishmania parasites impair the generation of cellular as well as mitochondrial reactive oxygen species (ROS), which is a major host defense mechanism against any invading pathogen. Mitochondrial uncoupling protein 2 (UCP2) is strongly induced in Leishmania infection, both at mRNA and protein levels, to suppress the mitochondrial ROS generation. In the present study we have demonstrated that L. donovani infection is associated with strong up-regulation of UCP2 at mRNA level which is the determining factor for its protein level upregulation. The transcriptional activation of UCP2 was mediated by increased nuclear translocation and DNA binding of sterol regulatory element binding protein 2 (SREBP2) and specificity protein 1 (Sp1) transcription factors with concomitant decrease of both the nuclear content and promoter occupancy of upstream stimulatory factor 1 (USF1). siRNA-mediated silencing of SREBP2 or Sp1 was associated with decreased UCP2 expression in infected macrophages. In contrast, downregulation of USF1 resulted in activated transcription of UCP2. L. donovani infection resulted in degradation of USF1 thereby facilitating SREBP2 binding which in turn assisted in the association of Sp1 with the promoter ultimately culminating in elevated transcription of UCP2.The international journal of biochemistry & cell biology 01/2014; · 4.89 Impact Factor