Regulatory mechanisms mediated by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in skin cancer

Considerable progress has been made during the past twenty years towards elucidating the role of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in skin cancer. In 1999, the original notion that PPARβ/δ was involved with epithelial cell function was postulated based on a correlation between PPARβ/δ expression and the induction of mRNAs encoding proteins that mediate terminal differentiation in keratinocytes. Subsequent studies definitively revealed that PPARβ/δ could induce terminal differentiation and inhibit proliferation of keratinocytes. Molecular mechanisms have since been discovered to explain how this nuclear receptor can be targeted for preventing and treating skin cancer. This includes the regulation of terminal differentiation, mitotic signaling, endoplasmic reticulum stress, and cellular senescence. Interestingly, the effects of activating PPARβ/δ can preferentially target keratinocytes with genetic mutations associated with skin cancer. This review provides the history and current understanding of how PPARβ/δ can be targeted for both non-melanoma skin cancer and melanoma, and postulates how future approaches that modulate PPARβ/δ signaling may be developed for the prevention and treatment of these diseases

Analysis of the peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) cistrome reveals novel co-regulatory role of ATF4

Abstract Background The present study coupled expression profiling with chromatin immunoprecipitation sequencing (ChIP-seq) to examine peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)-dependent regulation of gene expression in mouse keratinocytes, a cell type that expresses PPARβ/δ in high concentration. Results Microarray analysis elucidated eight different types of regulation that modulated PPARβ/δ-dependent gene expression of 612 genes ranging from repression or activation without an exogenous ligand, repression or activation with an exogenous ligand, or a combination of these effects. Bioinformatic analysis of ChIP-seq data demonstrated promoter occupancy of PPARβ/δ for some of these genes, and also identified the presence of other transcription factor binding sites in close proximity to PPARβ/δ bound to chromatin. For some types of regulation, ATF4 is required for ligand-dependent induction of PPARβ/δ target genes. Conclusions PPARβ/δ regulates constitutive expression of genes in keratinocytes, thus suggesting the presence of one or more endogenous ligands. The diversity in the types of gene regulation carried out by PPARβ/δ is consistent with dynamic binding and interactions with chromatin and indicates the presence of complex regulatory networks in cells expressing high levels of this nuclear receptor such as keratinocytes. Results from these studies are the first to demonstrate that differences in DNA binding of other transcription factors can directly influence the transcriptional activity of PPARβ/δ.http://deepblue.lib.umich.edu/bitstream/2027.42/112940/1/12864_2012_Article_4648.pd

Magnetic Dirac semimetal state of (Mn,Ge)Bi2_2Te4_4

For quantum electronics, the possibility to finely tune the properties of magnetic topological insulators (TIs) is a key issue. We studied solid solutions between two isostructural Z$_2$ TIs, magnetic MnBi$_2$Te$_4$ and nonmagnetic GeBi$_2$Te$_4$, with Z$_2$ invariants of 1;000 and 1;001, respectively. For high-quality, large mixed crystals of Ge$_x$Mn$_{1-x}$Bi$_2$Te$_4$, we observed linear x-dependent magnetic properties, composition-independent pairwise exchange interactions along with an easy magnetization axis. The bulk band gap gradually decreases to zero for $x$ from 0 to 0.4, before reopening for $x>0.6$, evidencing topological phase transitions (TPTs) between topologically nontrivial phases and the semimetal state. The TPTs are driven purely by the variation of orbital contributions. By tracing the x-dependent $6p$ contribution to the states near the fundamental gap, the effective spin-orbit coupling variation is extracted. As $x$ varies, the maximum of this contribution switches from the valence to the conduction band, thereby driving two TPTs. The gapless state observed at $x=0.42$ closely resembles a Dirac semimetal above the Neel temperature and shows a magnetic gap below, which is clearly visible in raw photoemission data. The observed behavior of the Ge$_x$Mn$_{1-x}$Bi$_2$Te$_4$ system thereby demonstrates an ability to precisely control topological and magnetic properties of TIs

Ligand Activation of Peroxisome Proliferator–Activated Receptor-β/δ and Inhibition of Cyclooxygenase-2 Enhances Inhibition of Skin Tumorigenesis

Ligand activation of peroxisome proliferator–activated receptor (PPAR)-β/δ and inhibition of cyclooxygenase-2 (COX-2) activity by nonsteroidal anti-inflammatory drugs can attenuate skin tumorigenesis. There is also evidence that attenuation of skin tumorigenesis by inhibition of COX-2 activity occurs through PPARβ/δ-independent mechanisms. The present study examined the hypothesis that combining ligand activation of PPARβ/δ with inhibition of COX-2 activity will cooperatively inhibit chemically induced skin tumor progression using both in vivo and ex vivo models. A two-stage chemical carcinogenesis bioassay was performed in wild-type and Pparβ/δ-null mice. After 22 weeks, cohorts of both mouse lines were divided into four experimental groups: (1) control, (2) topical application of the PPARβ/δ ligand GW0742, (3) dietary administration of the COX-2 inhibitor nimesulide, or (4) both GW0742 and nimesulide. Ligand activation of PPARβ/δ did not influence skin tumor progression, while a modest decrease in skin tumor multiplicity was observed with dietary nimesulide. Interestingly, the combined treatment of GW0742 and nimesulide increased the efficacy of the decrease in papilloma multiplicity for 6 weeks in wild-type mice, but this effect was not found at later time points and was not found in similarly treated Pparβ/δ-null mice. Neoplastic keratinocyte lines cultured with GW0742 and nimesulide also exhibited enhanced inhibition of cell proliferation coincident with increased expression of Keratin messenger RNAs. Results from these studies support the hypothesis that combining ligand activation of PPARβ/δ with inhibition of COX-2 activity can inhibit chemically induced skin tumor progression by modulating differentiation

Stable over-expression of PPARβ/δ and PPARγ to examine receptor signaling in human HaCaT keratinocytes

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) function and receptor cross-talk with other nuclear receptors, including PPARγ and retinoic acid receptors (RARs), was examined using stable human HaCaT keratinocyte cell lines over-expressing PPARβ/δ or PPARγ. Enhanced ligand-induced expression of two known PPAR target genes, adipocyte differentiation-related protein (ADRP) and angiopoietin-like protein 4 (ANGPTL4), was found in HaCaT keratinocytes over-expressing PPARβ/δ or PPARγ. Over-expression of PPARβ/δ did not modulate the effect of a PPARγ agonist on up-regulation of ADRP or ANGPTL4 mRNA in HaCaT keratinocytes. All-trans retinoic acid (atRA) increased expression of a known RAR target gene, yet despite a high ratio of fatty acid binding protein 5 (FABP5) to cellular retinoic acid binding protein II, did not increase expression of ANGPTL4 or 3-phosphoinositide-dependent-protein kinase 1 (PDPK1), even in HaCaT keratinocytes expressing markedly higher levels of PPARβ/δ. While PPARβ/δ-dependent attenuation of staurosporine-or UVB-induced poly (ADP-ribose) polymerase (PARP) cleavage was not observed, PPARβ/δ-and PPARγ-dependent repression of UVB-induced expression and secretion of inflammatory cytokines was found in HaCaT keratinocytes over-expressing PPARβ/δ or PPARγ. These studies suggest that FABP5 does not transport atRA or GW0742 to PPARβ/δ and promote anti-apoptotic activity by increasing expression of PDPK1, or that PPARβ/δ interferes with PPARγ transcriptional activity. However, these studies demonstrate that stable over-expression of PPARβ/δ or PPARγ significantly increases the efficacy of ligand activation and represses UVB-induced expression of tumor necrosis factor α (TNFα), interleukin 6 (IL6), or IL8 in HaCaT keratinocytes, thereby establishing an excellent model to study the functional role of these receptors in human keratinocytes