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Yoo, Taesik,Ham, Sun Ah,Lee, Won Jin,Hwang, Seon In,Park, Jin-A,Hwang, Jung Seok,Hur, Jinwoo,Shin, Ho-Chul,Han, Sung Gu,Lee, Chi-Ho,Han, Dong Wook,Paek, Kyung Shin,Seo, Han Geuk American Diabetes Association 2018 Diabetes Vol.67 No.3
<P>Peroxisome proliferator-activated receptor (PPAR) delta plays a pivotal role in metabolic homeostasis through its effect on insulin signaling. Although diverse genomic actions of PPAR delta are postulated, the specific molecular mechanisms whereby PPARd controls insulin signaling have not been fully elucidated. We demonstrate here that short-term activation of PPAR delta results in the formation of a stable complex with nuclear T-cell protein tyrosine phosphatase 45 (TCPTP45) isoform. This interaction of PPAR delta with TCPTP45 blocked translocation of TCPTP45 into the cytoplasm, thereby preventing its interaction with the insulin receptor, which inhibits insulin signaling. Interaction of PPAR delta with TCPTP45 blunted interleukin 6-induced insulin resistance, leading to retention of TCPTP45 in the nucleus, thereby facilitating deactivation of the signal transducer and activator of transcription 3 (STAT3)-suppressor of cytokine signaling 3 (SOCS3) signal. Finally, GW501516-activated PPAR delta improved insulin signaling and glucose intolerance in mice fed a high-fat diet through its interaction with TCPTP45. This novel interaction of PPAR delta constitutes the most upstream component identified of the mechanism downregulating insulin signaling.</P>
Ligand‐activated interaction of PPARδ with c‐Myc governs the tumorigenicity of breast cancer
Ham, Sun Ah,Kim, Eunsu,Yoo, Taesik,Lee, Won Jin,Youn, Ju Ho,Choi, Mi‐,Jung,Han, Sung Gu,Lee, Chi‐,Ho,Paek, Kyung Shin,Hwang, Jung Seok,Seo, Han Geuk Alan R. Liss, Inc 2018 International journal of cancer Vol.143 No.11
<P>Peroxisome proliferator‐activated receptor (PPAR) δ is a promising therapeutic target in metabolic and inflammatory disorders. However, its role in oncogenesis is controversial, and its therapeutic potential remains to be determined. In our study, we show that ligand‐activated PPARδ forms a complex with the proto‐oncogene product c‐Myc. The interaction of PPARδ with c‐Myc affected the transcriptional activity of c‐Myc and the expression of its target genes. The PPARδ‐dependent regulation of c‐Myc activity was associated with decreased tumorigenicity in breast cancer cells. Administration of the PPARδ ligand GW501516 inhibited tumor growth in xenograft model mice bearing MDA‐MB‐231 cells stably expressing wild‐type PPARδ, but not those expressing dominant‐negative PPARδ, by interfering with c‐Myc function through protein–protein interaction. Our results indicating that PPARδ forms an antitumorigenic complex with c‐Myc in the presence of ligand suggest a potential role of PPARδ in breast cancer development.</P>
Ham, Sun Ah,Hwang, Jung Seok,Kang, Eun Sil,Yoo, Taesik,Lim, Hyun Ho,Lee, Won Jin,Paek, Kyung Shin,Seo, Han Geuk Japan Society for Bioscience, Biotechnology, and A 2015 Bioscience, biotechnology, and biochemistry Vol.79 No.5
<P>Dalbergia odorifera T. Chen (Leguminosae), an indigenous medicinal herb, has been widely used in northern and eastern Asia to treat diverse diseases. Here, we investigated the anti-senescent effects of ethanolic extracts of Dalbergia odorifera (EEDO) in ultraviolet (UV) B-irradiated skin cells. EEDO significantly inhibited UVB-induced senescence of human keratinocytes in a concentration-dependent manner, concomitant with inhibition of reactive oxygen species (ROS) generation. UVB-induced increases in the levels of p53 and p21, biomarkers of cellular senescence, were almost completely abolished in the presence of EEDO. Sativanone, a major constituent of EEDO, also attenuated UVB-induced senescence and ROS generation in keratinocytes, indicating that sativanone is an indexing (marker) molecule for the anti-senescence properties of EEDO. Finally, treatment of EEDO to mice exposed to UVB significantly reduced ROS levels and the number of senescent cells in the skin. Thus, EEDO confers resistance to UVB-induced cellular senescence by inhibiting ROS generation in skin cells.</P>
PPARδ Inhibits UVB-Induced Secretion of MMP-1 through MKP-7-Mediated Suppression of JNK Signaling
Ham, Sun A,Kang, Eun S,Lee, Hanna,Hwang, Jung S,Yoo, Taesik,Paek, Kyung S,Park, Chankyu,Kim, Jin-Hoi,Lim, Dae-Seog,Seo, Han G The Society for Investigative Dermatology, Inc 2013 The Journal of investigative dermatology Vol.133 No.11
In the present study, we investigated the role of peroxisome proliferator–activated receptor (PPAR) δ in modulating matrix-degrading metalloproteinases and other mechanisms underlying photoaging processes in the skin. In human dermal fibroblasts (HDFs), activation of PPARδ by its specific ligand GW501516 markedly attenuated UVB-induced secretion of matrix metalloproteinase (MMP)-1, concomitant with decreased generation of reactive oxygen species. These effects were significantly reduced in the presence of PPARδ small interfering RNA and GSK0660. Furthermore, c-Jun N-terminal kinase (JNK), but not p38 or extracellular signal–regulated kinase, mediated PPARδ-dependent inhibition of MMP-1 secretion in HDFs exposed to UVB. PPARδ-mediated messenger RNA stabilization of mitogen-activated protein kinase phosphatase (MKP)-7 was responsible for the GW501516-mediated inhibition of JNK signaling. Inhibition of UVB-induced secretion of MMP-1 by PPARδ was associated with the restoration of types I and III collagen to levels approaching those in cells not exposed to UVB. Finally, in HR-1 hairless mice exposed to UVB, administration of GW501516 significantly reduced wrinkle formation and skin thickness, downregulated MMP-1 and JNK phosphorylation, and restored the levels of MKP-7, types I and III collagen. These results suggest that PPARδ-mediated inhibition of MMP-1 secretion prevents some effects of photoaging and maintains the integrity of skin by inhibiting the degradation of the collagenous extracellular matrix.