Auxiliary Kv␤ subunits form complexes with Kv1 family voltage-gated K؉ channels by binding to a part of the N terminus of channel polypeptide. This association influences expression and gating of these channels. Here we show that Kv4.3 proteins are associated with Kv␤2 subunits in the brain. Expression of Kv␤1 or Kv␤2 subunits does not affect Kv4.3 channel gating but increases current density and protein expression. The increase in Kv4.3 protein is larger at longer times after transfection, suggesting that Kv␤-associated channel proteins are more stable than those without the auxiliary subunits. This association between Kv4.3 and Kv␤ subunits requires the C terminus but not the N terminus of the channel polypeptide. Thus, Kv␤ subunits utilize diverse molecular interactions to stimulate the expression of Kv channels from different families.

Peroxisome proliferator-activated receptor (PPAR)-␥ and retinoic acid X receptor (RXR) heterodimer regulates cell growth and differentiation. Zinc finger transcription factor-9 (Zf9), whose phosphorylation promotes target genes, is a transcription factor essential for transactivation of the transforming growth factor (TGF)-␤1 gene. This study investigated whether activation of PPAR␥-RXR heterodimer inhibits TGF␤1 gene transcription and Zf9 phosphorylation and, if so, what signaling pathway regulates it. Either 15-deoxy-␦(12,14)-prostaglandin J 2 (PGJ 2 ) or 9-cis-retinoic acid (RA) treatment decreased the TGF␤1 mRNA level in L929 fibroblasts. PGJ 2 ϩ RA, compared with individual treatment alone, synergistically inhibited the TGF␤1 gene expression, which was abrogated by PPAR␥ antagonists. Likewise, PGJ 2 ϩ RA decreased luciferase expression from the TGF␤1 gene promoter. Promoter deletion analysis of the TGF␤1 gene revealed that pGL3-323 making up to Ϫ323-base pair region, but lacking PPAR-responsive elements, responded to PGJ 2 ϩ RA. PGJ 2 ϩ RA treatment inhibited the activity of p70 ribosomal S6 kinase-1 (S6K1), abolishing Zf9 phosphorylation at serine as did rapamycin [a mammalian target of rapamycin (mTOR) inhibitor]. Zf9 dephosphorylation by PGJ 2 ϩ RA was reversed by transfection of cells with the plasmid encoding constitutively active S6K1 (CA-S6K1). Transfection with dominant negative S6K1 inhibited the TGF␤1 gene. TGF␤1 gene repression by PGJ 2 ϩ RA was consistently antagonized by CA-S6K1. Ectopic expression of PPAR␥1 and RXR␣ repressed pGL3-323 transactivation with S6K1 inhibition, which was abrogated by CA-S6K1 transfection. PGJ 2 ϩ RA induced phosphatase and tensin homolog deleted on chromosome 10 (PTEN), whose overexpression repressed the TGF␤1 gene through S6K1 inhibition, decreasing extracellular signal-regulated kinase 1/2-90-kDa ribosomal S6 kinase 1 and Akt-mTOR phosphorylations. Data indicate that activation of PPAR␥-RXR heterodimer represses the TGF␤1 gene and induces Zf9 dephosphorylation via PTEN-mediated S6K1 inhibition, providing insight into pharmacological manipulation of the TGF␤1 gene regulation.The human transforming growth factor-␤ isoforms constitute extracellular signaling molecules that have antiproliferative effects on mammalian cells, promoting the expression of cell adhesion molecules and extracellular matrix proteins.In particular, transforming growth factor (TGF)-␤1 serves as a key fibrogenic mediator that can enhance extracellular matrix deposition and inhibit collagenase activity during fibrogenesis (Friedman, 1993). The regulation of TGF␤1 expression is complex and occurs at multiple levels, orchestrated transcriptionally by the multiple transcription factors and post-translationally by maturation of the precursors bound with TGF␤1 binding proteins (Kim et al., 1989a;Oklu and Hesketh, 2000).The peroxisome proliferator-activated receptors (PPARs) are transcription factors that are members of the nuclear This work was supported by

A bstractResveratrol has been show n to possess antioxidant and anticancer activities, but little is know n on the effect of resveratrol derivatives. Recently w e have isolated resveratrol and its dim ers and trim ers from peony (Paeonia lactiflora) seeds, and reported their strong antioxidant and cytotoxic activity. In the present study

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Abbreviations: HWE, Hardy-Weinberg equilibrium; LD, linkage disequilibrium; MAF, minor allele frequency; ONFH, osteonecrosis of the femoral head; SNP, single nucleotide polymorphism AbstractMultiple factors have been implicated in the development of osteonecrosis of the femoral head (ONFH). In particular, non-traumatic ONFH is directly or indirectly related to injury of the vascular supply to the femoral head. Thus, hypoxia in the femoral head caused by impaired blood flow may be an important risk factor for ONFH. In this study, we investigated whether genetic variations of angiogenesis-and hypoxia-related genes contribute to an increased risk for the development of ONFH. Candidate genes were selected based on known hypoxia and angiogenesis pathways. An association study was performed using an Affymetrix Targeted Genotyping 3K Chip array with 460 ONFH patients and 300 control subjects. We showed that single nucleotide polymorphisms (SNPs) in the genes TF, VEGFC, IGFBP3, and ACE were associated with an increased risk of ONFH. On the other hand, SNPs in the KDR and NRP1 genes were associated with protection against ONFH. The most important finding was that one SNP (rs2453839) in the IGFBP3 gene was significantly associated with a higher risk of ONFH (P = 0.0061, OR 7.74). In subgroup analysis, most candidate gene variations that were associated with ONFH occurred in the idiopathic subgroup. Among other SNPs, ACE SNPs were associated with steroid-induced ONFH (P = 0.0018-0.0037, OR ＞ 3). Collectively, our findings suggest that genetic variations in angiogenesis-and hypoxia-related genes may help to identify susceptibility factors for the development of ONFH in the Korean population.