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Science 20 December 1996:
Vol. 274. no. 5295, pp. 2100 - 2103
DOI: 10.1126/science.274.5295.2100
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Reports

Inhibition of Adipogenesis Through MAP Kinase-Mediated Phosphorylation of PPARgamma

Erding Hu, Jae Bum Kim, Pasha Sarraf, Bruce M., Spiegelman *

Adipocyte differentiation is an important component of obesity and other metabolic diseases. This process is strongly inhibited by many mitogens and oncogenes. Several growth factors that inhibit fat cell differentiation caused mitogen-activated protein (MAP) kinase-mediated phosphorylation of the dominant adipogenic transcription factor peroxisome proliferator-activated receptor gamma  (PPARgamma ) and reduction of its transcriptional activity. Expression of PPARgamma with a nonphosphorylatable mutation at this site (serine-112) yielded cells with increased sensitivity to ligand-induced adipogenesis and resistance to inhibition of differentiation by mitogens. These results indicate that covalent modification of PPARgamma by serum and growth factors is a major regulator of the balance between cell growth and differentiation in the adipose cell lineage.

Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
*   To whom correspondence should be addressed.

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Genetics 165, 1779-1791
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Dependence of Peroxisome Proliferator-activated Receptor Ligand-induced Mitogen-activated Protein Kinase Signaling on Epidermal Growth Factor Receptor Transactivation.
O. S. Gardner, B. J. Dewar, H. S. Earp, J. M. Samet, and L. M. Graves (2003)
J. Biol. Chem. 278, 46261-46269
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Adipogenic differentiating agents regulate expression of fatty acid binding protein and CD36 in the J744 macrophage cell line.
L. Sun, A. C. Nicholson, D. P. Hajjar, A. M. Gotto Jr., and J. Han (2003)
J. Lipid Res. 44, 1877-1886
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Control of COX-2 Gene Expression through Peroxisome Proliferator-Activated Receptor {gamma} in Human Cervical Cancer Cells.
S. Han, H. Inoue, L. C. Flowers, and N. Sidell (2003)
Clin. Cancer Res. 9, 4627-4635
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Transcriptional Profiling of Targets for Combination Therapy of Lung Carcinoma with Paclitaxel and Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase Inhibitor.
D. J. Taxman, J. P. MacKeigan, C. Clements, D. T. Bergstralh, and J. P-Y. Ting (2003)
Cancer Res. 63, 5095-5104
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Peroxisome Proliferator-activated Receptor-{gamma} Represses GLUT4 Promoter Activity in Primary Adipocytes, and Rosiglitazone Alleviates This Effect.
M. Armoni, N. Kritz, C. Harel, F. Bar-Yoseph, H. Chen, M. J. Quon, and E. Karnieli (2003)
J. Biol. Chem. 278, 30614-30623
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The Metabolic Syndrome: Peroxisome Proliferator-Activated Receptor {gamma} and Its Therapeutic Modulation.
M. Gurnell, D. B. Savage, V. K. K. Chatterjee, and S. O'Rahilly (2003)
J. Clin. Endocrinol. Metab. 88, 2412-2421
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Mechanism of Adult Primitive Mesenchymal ST-13 Preadipocyte Differentiation.
Y. Yajima, M. Sato, M. Sumida, and S. Kawashima (2003)
Endocrinology 144, 2559-2565
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PPAR{gamma} and PPAR{delta} negatively regulate specific subsets of lipopolysaccharide and IFN-{gamma} target genes in macrophages.
J. S. Welch, M. Ricote, T. E. Akiyama, F. J. Gonzalez, and C. K. Glass (2003)
PNAS 100, 6712-6717
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15d-PGJ2 and Rosiglitazone Suppress Janus Kinase-STAT Inflammatory Signaling through Induction of Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 in Glia.
E. J. Park, S. Y. Park, E.-h. Joe, and I. Jou (2003)
J. Biol. Chem. 278, 14747-14752
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Inhibition of Proliferation and Estrogen Receptor Signaling by Peroxisome Proliferator-activated Receptor {gamma} Ligands in Uterine Leiomyoma.
K. D. Houston, J. A. Copland, R. R. Broaddus, M. M. Gottardis, S. M. Fischer, and C. L. Walker (2003)
Cancer Res. 63, 1221-1227
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Troglitazone, a Peroxisome Proliferator-activated Receptor gamma (PPARgamma ) Ligand, Selectively Induces the Early Growth Response-1 Gene Independently of PPARgamma . A NOVEL MECHANISM FOR ITS ANTI-TUMORIGENIC ACTIVITY.
S. J. Baek, L. C. Wilson, L. C. Hsi, and T. E. Eling (2003)
J. Biol. Chem. 278, 5845-5853
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Differential Roles of Smad1 and p38 Kinase in Regulation of Peroxisome Proliferator-activating Receptor gamma during Bone Morphogenetic Protein 2-induced Adipogenesis.
K. Hata, R. Nishimura, F. Ikeda, K. Yamashita, T. Matsubara, T. Nokubi, and T. Yoneda (2003)
Mol. Biol. Cell 14, 545-555
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Peroxisome Proliferator-activated Receptor gamma (PPARgamma ) as a Molecular Target for the Soy Phytoestrogen Genistein.
Z.-C. Dang, V. Audinot, S. E. Papapoulos, J. A. Boutin, and C. W. G. M. Lowik (2003)
J. Biol. Chem. 278, 962-967
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Differential Regulation of Lipogenesis and Leptin Production by Independent Signaling Pathways and Rosiglitazone During Human Adipocyte Differentiation.
N. G. Patel, J. C. Holder, S. A. Smith, S. Kumar, and M. C. Eggo (2003)
Diabetes 52, 43-50
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Calcineurin Mediates the Calcium-dependent Inhibition of Adipocyte Differentiation in 3T3-L1 Cells.
J. W. Neal and N. A. Clipstone (2002)
J. Biol. Chem. 277, 49776-49781
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Activation of MEK/ERK Signaling Promotes Adipogenesis by Enhancing Peroxisome Proliferator-activated Receptor gamma (PPARgamma ) and C/EBPalpha Gene Expression during the Differentiation of 3T3-L1 Preadipocytes.
D. Prusty, B.-H. Park, K. E. Davis, and S. R. Farmer (2002)
J. Biol. Chem. 277, 46226-46232
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Opposing Effects of 15-Lipoxygenase-1 and -2 Metabolites on MAPK Signaling in Prostate. ALTERATION IN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR gamma.
L. C. Hsi, L. C. Wilson, and T. E. Eling (2002)
J. Biol. Chem. 277, 40549-40556
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APC-dependent suppression of colon carcinogenesis by PPARgamma.
G. D. Girnun, W. M. Smith, S. Drori, P. Sarraf, E. Mueller, C. Eng, P. Nambiar, D. W. Rosenberg, R. T. Bronson, W. Edelmann, et al. (2002)
PNAS 99, 13771-13776
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Tumor Necrosis Factor-{alpha} Stimulates Lipolysis in Differentiated Human Adipocytes Through Activation of Extracellular Signal-Related Kinase and Elevation of Intracellular cAMP.
H. H. Zhang, M. Halbleib, F. Ahmad, V. C. Manganiello, and A. S. Greenberg (2002)
Diabetes 51, 2929-2935
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Inhibition of Phosphorylation of BAD and Raf-1 by Akt Sensitizes Human Ovarian Cancer Cells to Paclitaxel.
S. Mabuchi, M. Ohmichi, A. Kimura, K. Hisamoto, J. Hayakawa, Y. Nishio, K. Adachi, K. Takahashi, E. Arimoto-Ishida, Y. Nakatsuji, et al. (2002)
J. Biol. Chem. 277, 33490-33500
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The Phosphorylation Site Located in the A Region of Retinoic X Receptor alpha Is Required for the Antiproliferative Effect of Retinoic Acid (RA) and the Activation of RA Target Genes in F9 Cells.
J. Bastien, S. Adam-Stitah, J.-L. Plassat, P. Chambon, and C. Rochette-Egly (2002)
J. Biol. Chem. 277, 28683-28689
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Oxidized omega-3 fatty acids in fish oil inhibit leukocyte-endothelial interactions through activation of PPARalpha.
S. Sethi, O. Ziouzenkova, H. Ni, D. D. Wagner, J. Plutzky, and T. N. Mayadas (2002)
Blood 100, 1340-1346
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