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Dive into the research topics where Julie B. Stimmel is active.

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Featured researches published by Julie B. Stimmel.


Nature | 2002

Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARα

H. Eric Xu; Thomas B. Stanley; Valerie G. Montana; Millard H. Lambert; Barry George Shearer; Jeffery E. Cobb; David D. McKee; Cristin M. Galardi; Kelli D. Plunket; Robert T. Nolte; Derek J. Parks; John T. Moore; Steven A. Kliewer; Timothy M. Willson; Julie B. Stimmel

Repression of gene transcription by nuclear receptors is mediated by interactions with co-repressor proteins such as SMRT and N-CoR, which in turn recruit histone deacetylases to the chromatin. Aberrant interactions between nuclear receptors and co-repressors contribute towards acute promyelocytic leukaemia and thyroid hormone resistance syndrome. The binding of co-repressors to nuclear receptors occurs in the unliganded state, and can be stabilized by antagonists. Here we report the crystal structure of a ternary complex containing the peroxisome proliferator-activated receptor-α ligand-binding domain bound to the antagonist GW6471 and a SMRT co-repressor motif. In this structure, the co-repressor motif adopts a three-turn α-helix that prevents the carboxy-terminal activation helix (AF-2) of the receptor from assuming the active conformation. Binding of the co-repressor motif is further reinforced by the antagonist, which blocks the AF-2 helix from adopting the active position. Biochemical analyses and structure-based mutagenesis indicate that this mode of co-repressor binding is highly conserved across nuclear receptors.


Proceedings of the National Academy of Sciences of the United States of America | 2003

The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-δ to induce apoptosis in colorectal cancer cells

Imad Shureiqi; Wei Jiang; Xiangsheng Zuo; Yuanqing Wu; Julie B. Stimmel; Lisa M. Leesnitzer; Jeffrey S. Morris; Hui Zhen Fan; Susan M. Fischer; Scott M. Lippman

Diminished apoptosis, a critical event in tumorigenesis, is linked to down-regulated 15-lipoxygenase-1 (15-LOX-1) expression in colorectal cancer cells. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which is the primary product of 15-LOX-1 metabolism of linoleic acid, restores apoptosis. Nonsteroidal antiinflammatory drugs (NSAIDs) transcriptionally up-regulate 15-LOX-1 expression to induce apoptosis. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for linoleic and arachidonic acid metabolites. PPAR-δ promotes colonic tumorigenesis. NSAIDs suppress PPAR-δ activity in colon cancer cells. The mechanistic relationship between 15-LOX-1 and PPAR-δ was previously unknown. Our current study shows that (i) 13-S-HODE binds to PPAR-δ, decreases PPAR-δ activation, and down-regulates PPAR-δ expression in colorectal cancer cells; (ii) the induction of 15-LOX-1 expression is a critical step in NSAID down-regulation of PPAR-δ and the resultant induction of apoptosis; and (iii) PPAR-δ is an important signaling receptor for 13-S-HODE-induced apoptosis. The in vivo relevance of these mechanistic findings was demonstrated in our tumorigenesis studies in nude mouse xenograft models. Our findings indicate that the down-regulation of PPAR-δ by 15-LOX-1 through 13-S-HODE is an apoptotic signaling pathway that is activated by NSAIDs.


Oncogene | 2006

Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity

Xiangsheng Zuo; Yuanqing Wu; Jeffrey S. Morris; Julie B. Stimmel; Lisa M. Leesnitzer; Susan M. Fischer; Scott M. Lippman; Imad Shureiqi

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that strongly influence molecular events in normal and cancer cells. PPAR-beta/delta (PPAR-b/d) overexpression suppresses the activity of PPAR-gamma (PPAR-g) and PPAR-alpha. This interaction has been questioned, however, by studies with synthetic ligands of PPARs in PPAR-b/d-null cells, and it is not known whether an interaction between PPAR-b/d and PPAR-g exists, especially in relation to the signaling by natural PPAR ligands. Oxidative metabolites of linoleic and arachidonic acids are natural ligands of PPARs. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), the main product of 15-lipoxygenase-1 (15-LOX-1) metabolism of linoleic acid, downregulates PPAR-b/d. We tested (a) whether PPAR-b/d expression modulates PPAR-g activity in experimental models of the loss and gain of PPAR-b/d function in colon cancer cells and (b) whether 15-LOX-1 formation of 13-S-HODE influences the interaction between PPAR-b/d and PPAR-g. We found that (a) 15-LOX-1 formation of 13-S-HODE promoted PPAR-g activity, (b) PPAR-b/d expression suppressed PPAR-g activity in models of both loss and gain of PPAR-b/d function, (c) 15-LOX-1 activated PPAR-g by downregulating PPAR-b/d, and (d) 15-LOX-1 expression induced apoptosis in colon cancer cells via modulating PPAR-b/d suppression of PPAR-g. These findings elucidate a novel mechanism of the signaling by natural ligands of PPARs, which involves modulating the interaction between PPAR-b/d and PPAR-g.


Biochemical Journal | 2002

Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors

Philippe Thuillier; Alan R. Brash; James P. Kehrer; Julie B. Stimmel; Lisa M. Leesnitzer; Peiying Yang; Robert A. Newman; Susan M. Fischer

Lipoxygenase (LOX) metabolites from arachidonic acid and linoleic acid have been implicated in atherosclerosis, inflammation, keratinocyte differentiation and tumour progression. We previously showed that peroxisome proliferator-activated receptors (PPARs) play a role in keratinocyte differentiation and that the PPARalpha ligand 8S-hydroxyeicosatetraenoic acid is important in this process. We hypothesized that blocking LOX activity would block PPAR-mediated keratinocyte differentiation. Three LOX inhibitors, nordihydroguaiaretic acid, quercetin and morin, were studied for their effects on primary keratinocyte differentiation and PPAR activity. All three LOX inhibitors blocked calcium-induced expression of the differentiation marker keratin 1. In addition, activity of a PPAR-responsive element was inhibited in the presence of all three inhibitors, and this effect was mediated primarily through PPARalpha and PPARgamma. LOX inhibitors decreased the activity of a chimaeric PPAR-Gal4-ligand-binding domain reporter system and this effect was reversed by addition of PPAR ligands. Ligand-binding studies revealed that the LOX inhibitors bind directly to PPARs and demonstrate a novel mechanism for these inhibitors in altering PPAR-mediated gene expression.


Free Radical Biology and Medicine | 2011

γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer

Sharon Campbell; Brittney Rudder; Regenia Phillips; Sarah Whaley; Julie B. Stimmel; Lisa M. Leesnitzer; Janet Lightner; Sophie Dessus-Babus; Michelle Duffourc; William L. Stone; David G. Menter; Robert A. Newman; Peiying Yang; Bharat B. Aggarwal; Koyamangalath Krishnan

Regions along the Mediterranean and in southern Asia have lower prostate cancer incidence compared to the rest of the world. It has been hypothesized that one of the potential contributing factors for this low incidence includes a higher intake of tocotrienols. Here we examine the potential of γ-tocotrienol (GT3) to reduce prostate cancer proliferation and focus on elucidating pathways by which GT3 could exert a growth-inhibitory effect on prostate cancer cells. We find that the γ and δ isoforms of tocotrienol are more effective at inhibiting the growth of prostate cancer cell lines (PC-3 and LNCaP) compared with the γ and δ forms of tocopherol. Knockout of PPAR-γ and GT3 treatment show inhibition of prostate cancer cell growth, through a partially PPAR-γ-dependent mechanism. GT3 treatment increases the levels of the 15-lipoxygenase-2 enzyme, which is responsible for the conversion of arachidonic acid to the PPAR-γ-activating ligand 15-S-hydroxyeicosatrienoic acid. In addition, the latent precursor and the mature forms of TGFβ2 are down-regulated after treatment with GT3, with concomitant disruptions in TGFβ receptor I, SMAD-2, p38, and NF-κB signaling.


Nutrition and Cancer | 2009

Gamma tocopherol upregulates the expression of 15-S-HETE and induces growth arrest through a PPAR gamma-dependent mechanism in PC-3 human prostate cancer cells.

Sharon Campbell; Phillip R. Musich; Sarah Whaley; Julie B. Stimmel; Lisa M. Leesnitzer; Sophie Dessus-Babus; Michelle Duffourc; William L. Stone; Robert A. Newman; Peiying Yang; Koyamangalath Krishnan

Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer. Our previous studies in the colon have demonstrated that γ-tocopherol treatment could upregulate the expression of peroxisome proliferator-activated preceptors (PPAR) γ, a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation. In this study, we explored the possibility that γ-tocopherol could induce growth arrest in PC-3 prostate cancer cells through the regulation of fatty acid metabolism. Growth arrest (40%) and PPAR γ mRNA and protein upregulation was achieved with γ-tocopherol within 6 h. γ-Tocopherol-mediated growth arrest was demonstrated to be PPAR γ dependent using the agonist GW9662 and a PPAR γ dominant negative vector. γ-tocopherol was shown not to be a direct PPAR γ ligand, but rather 15-S-HETE (an endogenous PPAR γ ligand) was upregulated by γ-tocopherol treatment. 15-Lipoxygenase-2, a tumor suppressor and the enzyme that converts arachidonic acid to 15-S-HETE, was upregulated at 3 h following γ-tocopherol treatment. Expression of proteins downstream of the PPAR γ pathway were examined. Cyclin D1, cyclin D3, bcl-2, and NFκ B proteins were found to be downregulated following γ-tocopherol treatment. These data demonstrate that the growth arrest mediated by γ-tocopherol follows a PPAR-γ-dependent mechanism.


PLOS ONE | 2011

Lysophosphatidic acid activates peroxisome proliferator activated receptor-γ in CHO cells that over-express glycerol 3-phosphate acyltransferase-1

Cliona Stapleton; Douglas G. Mashek; Shuli Wang; Cynthia A. Nagle; Gary W. Cline; Philippe Thuillier; Lisa M. Leesnitzer; Lei O. Li; Julie B. Stimmel; Gerald I. Shulman; Rosalind A. Coleman

Lysophosphatidic acid (LPA) is an agonist for peroxisome proliferator activated receptor-γ (PPARγ). Although glycerol-3-phosphate acyltransferase-1 (GPAT1) esterifies glycerol-3-phosphate to form LPA, an intermediate in the de novo synthesis of glycerolipids, it has been assumed that LPA synthesized by this route does not have a signaling role. The availability of Chinese Hamster Ovary (CHO) cells that stably overexpress GPAT1, allowed us to analyze PPARγ activation in the presence of LPA produced as an intracellular intermediate. LPA levels in CHO-GPAT1 cells were 6-fold higher than in wild-type CHO cells, and the mRNA abundance of CD36, a PPARγ target, was 2-fold higher. Transactivation assays showed that PPARγ activity was higher in the cells that overexpressed GPAT1. PPARγ activity was enhanced further in CHO-GPAT1 cells treated with the PPARγ ligand troglitazone. Extracellular LPA, phosphatidic acid (PA) or a membrane-permeable diacylglycerol had no effect, showing that PPARγ had been activated by LPA generated intracellularly. Transient transfection of a vector expressing 1-acylglycerol-3-phosphate acyltransferase-2, which converts endogenous LPA to PA, markedly reduced PPARγ activity, as did over-expressing diacylglycerol kinase, which converts DAG to PA, indicating that PA could be a potent inhibitor of PPARγ. These data suggest that LPA synthesized via the glycerol-3-phosphate pathway can activate PPARγ and that intermediates of de novo glycerolipid synthesis regulate gene expression.


Cancer Immunology, Immunotherapy | 2003

Adenocarcinoma cells exposed in vitro to Navelbine or Taxol increase Ep-CAM expression through a novel mechanism

Linda M. Thurmond; Julie B. Stimmel; Adrienne C. Ingram; Christian H. Ryan; Doris Murray; Derek J. Eberwein; Sam M. Witherspoon; Vincent C. Knick

Ep-CAM antigen expression was shown to vary by phase across the cell cycle. Following pretreatment of various adenocarcinoma cells in culture with clinically relevant concentrations of vinorelbine tartrate (Navelbine) or paclitaxel (Taxol), cell surface expression of Ep-CAM antigen increased by two- to ten-fold compared to that of untreated control cells and was associated with arrest of cell cycle progression and accumulation of cells in the S and G2/M phases. We demonstrated that increases in cell surface antigen expression resulted in improved biological effectiveness of the targeting antibody as measured in vitro by antibody-dependent cellular cytotoxicity and in vivo by enhanced antibody targeting to Ep-CAM-expressing xenografts in mice pretreated with Navelbine. No effect on cell cycle progression or Ep-CAM antigen expression was seen with human interferon-α and interferon-γ, agents that increase gene expression of various tumor and normal antigens and may upregulate some antigens. Thus, the upregulation of cell surface Ep-CAM expression following pretreatment with G2/M blockers is through a novel mechanism involving residence time of the antigen on the cell surface. This significant increase in Ep-CAM expression appears to be tumor-specific since we saw no increase in antigen expression on normal epithelial cells. Studies to reveal relative internalization rates suggest that the increase in cell surface expression of Ep-CAM following pretreatment with G2/M blockers is a consequence of an inhibition of normal cycles of antigen endocytosis and expression on the cell surface. The present work provides a mechanism for the improved clinical efficacy of therapeutic antibodies used in combination with traditional cell cycle-specific chemotherapeutic drugs.


Science | 1999

Bile Acids: Natural Ligands for an Orphan Nuclear Receptor

Derek J. Parks; Steven G. Blanchard; Randy K. Bledsoe; Gyan Chandra; Thomas G. Consler; Steven A. Kliewer; Julie B. Stimmel; Timothy M. Willson; Ann Marie Zavacki; David D. Moore; Jürgen M. Lehmann


Journal of Biological Chemistry | 2000

Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands.

Linda B. Moore; Derek J. Parks; Stacey A. Jones; Randy K. Bledsoe; Thomas G. Consler; Julie B. Stimmel; Bryan Goodwin; Christopher Liddle; Steven G. Blanchard; Timothy M. Willson; Jon L. Collins; Steven A. Kliewer

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Steven A. Kliewer

University of Texas Southwestern Medical Center

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