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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.

Adipose differentiation is influenced by a large number of mitogens and growth factors (1). In general, polypeptides that stimulate cell growth block fat cell differentiation. Platelet-derived growth factor, epidermal growth factor (EGF), fibroblast growth factor, and tumor promoters all inhibit fat cell differentiation in culture or in vivo (2). Various cytokines, including tumor necrosis factor-alpha (TNF-alpha ), interleukin-1 (IL-1), IL-6, transforming growth factor-beta , and interferon-gamma also inhibit adipogenesis (3). Insulin has a prominent and complex role in the development of adipose cells, serving as a growth or differentiation factor depending on the specific cell type. Adipose cell precursors (preadipocytes), which express small amounts of insulin receptors, generally require insulin or insulinlike growth factor-1 for optimal differentiation (4). Adipose cells, which contain large numbers of insulin receptors but are postmitotic, respond to insulin with a lipogenic response as a result of the activation of lipogenic enzymes and the stimulation of Glut4-mediated glucose transport (5). In contrast, fibroblasts that express ectopically large amounts of insulin receptors usually respond to insulin with cell growth rather than differentiation (6).

Two families of factors are especially prominent in the transcriptional control of adipogenesis: the PPARs and C/EBPs. PPARgamma is a member of the nuclear hormone receptor family that is expressed preferentially in adipose tissue (7). It is expressed in small amounts in preadipocytes, and its synthesis is increased during the process of adipogenesis (8). PPARgamma binds specific ligands, including synthetic antidiabetic thiazolidinediones and 15-deoxy-Delta 12,14prostaglandin J2 (9), resulting in a full and powerful adipogenic response. Thus, PPARgamma appears to be a key component in the determination and differentiation process in vivo (9, 10).

Ectopic expression of C/EBP-beta and C/EBP-delta stimulates adipogenesis in fibroblasts as well (11, 12). This occurs through the C/EBP-mediated expression of PPARgamma (12). Adipogenesis induced by C/EBP-beta and C/EBP-delta requires a PPARgamma ligand (13). Expression of large amounts of C/EBP-alpha also promotes fat cell differentiation (14). However, when expressed at more physiological amounts, C/EBP-alpha can synergize with PPARgamma in the promotion of fat cell differentiation of fibroblasts or myoblasts (10, 15). Cross-regulation between PPARgamma and the C/EBPs may be crucial in maintaining the differentiated state of adipocytes (16).

Growth factor inhibition of adipogenesis might occur through effects on PPARgamma . To investigate this, we treated cells with various mitogens and examined their effects on PPARgamma ectopically expressed in two established lines of fibroblasts: NIH 3T3 cells, which have small amounts of insulin receptors, or Rat-1 cells that ectopically express the insulin receptor (Rat-IR cells). Rat-IR cells respond to insulin with a mitogenic response but no adipogenesis, whereas insulin promotes the differentiation of the NIH-PPARgamma cells (10). PPARgamma migrates as two closely spaced bands on an SDS-polyacrylamide gel, with the lower form being the predominant species (Fig. 1A). Stimulation of Rat-IR cells with EGF, 12-O-tetradecanoylphorbol-13-acetate (TPA), serum, or insulin for 30 min caused a reduction in the amount of the lower migrating species and an increase in the amount of the upper species (Fig. 1A, top panel). TNF-alpha treatment did not cause this mobility shift. An identical mobility shift was seen in NIH-PPARgamma cells treated with TPA or serum, but not with insulin (Fig. 1A, bottom panel). The mobility shift could be detected within 5 min after treatment of cells with insulin in Rat-IR cells and persisted for at least 4 hours (Fig. 1B). Treatment of cell extracts with calf intestinal alkaline phosphatase uniformly converted PPARgamma into the form of higher mobility (Fig. 1B), suggesting that the protein in the upper band is phosphorylated. To confirm directly that PPARgamma is phosphorylated, we metabolically labeled cells with [35S]methionine and 32PO4 and immunoprecipitated PPARgamma . Phosphate was preferentially associated with the upper form of PPARgamma , and the intensity of the upper band was increased upon insulin treatment (Fig. 1C).


Fig. 1. Modification of PPARgamma in response to mitogenic stimulation. (A) Transfection of PPARgamma 2 into Rat-IR and NIH 3T3 cells, growth factor stimulation, SDS-polyacrylamide gel electrophoresis (PAGE), and protein immunoblots were performed as described (26). PPARgamma 2 (shown with two arrows) migrates as two closely spaced bands with a molecular mass of sim 55 kD. Lanes 1 to 6 are extracts from Rat-IR cells and lanes 7 to 11 are from NIH 3T3 cells. Treatments with the indicated mitogens were for 30 min. Ser., serum; Ins., insulin; IVT, in vitro-translated PPARgamma 2; N.S., nonspecific bands. (B) Transfected Rat-IR cells were treated with insulin (5 µg/ml) and harvested at different time points as in (A). Lysates were treated with calf intestine alkaline phosphatase (AP) as described (27). Proteins in treated (+) and untreated (-) lysates along with the original lysate were separated by SDS-PAGE and immunoblotted. Lane 1 (IVT), 1 µl of in vitro-translated PPARgamma 2 (TNT kit, Promega). Lanes 2 to 5 are undialyzed lysates stimulated with insulin for 0, 5 min (m), 30 min, and 4 hours (h), respectively. Lane pairs 6-7, 8-9, 10-11, and 12-13 are dialyzed samples at different time points with (+) or without (-) AP treatment. (C) Transfected Rat-IR cells were metabolically labeled with [35S]methionine (1 mCi/ml) or 32P (2 mCi/ml) for 4 hours and were then stimulated with insulin (5 µg/ml) for 30 min. Cells were lysed with RIPA as described and immunoprecipitations (IPs) were done in RIPA buffer as standard procedure. 35S-labeled in vitro-translated PPARgamma (1 µl) was used as positive control for IP (IVT, lanes 1 and 5). Lanes 2 and 3 are IPs from 35S-labeled extracts without (-) or with (+) insulin stimulation. Lanes 6 and 7 are IPs from 32P-labeled extracts without or with insulin stimulation. IPs with preimmune serums did not contain any bands in the 40- to 60-kD range. [View Larger Versions of these Images (160K GIF file)]

Preliminary mapping of the phosphorylation site associated with this mobility shift was carried out by examination of a series of NH2-terminal deletions (17). The key region was localized near a serine residue (Ser112) that is present in a sequence (PASP) that matches a consensus sequence for MAP kinase (PXSP), where X represents neutral or basic amino acids (18, 19). Indeed, treatment of wild-type PPARgamma in vitro with MAP kinase (specifically, Erk1, also called p44) caused a mobility shift of wild-type PPARgamma , but it did not alter the mobility of an allele containing a serine-to-alanine mutation at position 112 (S112A, Fig. 2A). This mutation also blocked the ability of insulin, EGF, TPA, or serum to cause this mobility shift in vivo (Fig. 2B). In metabolic labeling experiments, this mutation blocked the ability of insulin and TPA to induce phosphorylation of PPARgamma in Rat-IR cells (17). We also tested several agents that inhibit MAP kinase activity. PD98059 inhibits MAP kinases through direct inhibition of MAP kinase kinase (MEK) and completely prevented the mobility shift (Fig. 2C). Forskolin and 8-bromo-adenosine 3',5'-monophosphate (8Br-cAMP), although not specific agents, also inhibit activation of MAP kinases. No mobility was seen when cells were incubated with them. These data indicate that multiple growth factors all cause a phosphorylation of PPARgamma on a MAP kinase consensus site at Ser112 that can be mediated, at least in some instances, by the classical MAP kinases.


Fig. 2. Phosphorylation of PPARgamma by MAP kinase in vitro and in vivo. (A) Mutant PPARgamma was constructed by overlapping polymerase chain reaction (PCR) and verified by sequencing. In vitro-translated wild-type (WT) and mutant (S112A) PPARgamma 2 were treated with active bacterial-synthesized glutathione-S-transferase (GST)-MAP kinase (Erk-1) fusion protein and resolved by SDS-PAGE followed by immunoblotting. Double arrows indicate PPARgamma 2. (B) Rat-IR cells were transfected with wild-type or S112A mutant PPARgamma and treated with various mitogens for 30 min as described (26). Cell lysates were separated by SDS-PAGE and immunoblotted with antibody to PPARgamma . Lane 1 is in vitro-translated PPARgamma . Lanes 2 to 6 are lysates from cells transfected with wild-type PPARgamma 2 left untreated (-) or treated with insulin, EGF, TPA, or 30% serum, respectively. Lanes 7 to 11 are lysates from cells transfected with mutant PPARgamma 2 left untreated or treated with the indicated mitogens. (C) Rat-IR cells transfected with wild-type PPARgamma 2 were treated with PD98059 (PD) (50 µM), forskolin (For.) (10 µM), or 8Br-cAMP (2 mM) for 30 min before being stimulated (+) with insulin (5 µg/ml) or left unstimulated (-), and cell lysates were immunoblotted as described (26). Lane 1 is 1 µl of in vitro-translated PPARgamma 2. Lanes 2 and 3 are control lysates without or with insulin stimulation. [View Larger Versions of these Images (160K GIF file)]

To address the consequences of the Ser112 phosphorylation on PPARgamma function, we examined transcriptional and adipogenic activity of the wild-type and mutant alleles. Mutation of Ser112 to Ala112 had no effect on the nuclear localization, affinity for retinoid X receptor alpha  (RXRalpha ), or DNA binding activity of PPARgamma (17). However, differences were observed between wild-type and mutant PPARgamma in transactivation assays. Without ligand treatment, wild-type and S112A PPARgamma stimulated similar low levels of transcriptional activity (Fig. 3). A thiazolidinedione ligand, pioglitazone, stimulated a large increase in the activity of both alleles. Addition of the tumor promoter (TPA) caused an 80% decrease in the effect of pioglitazone on wild-type PPARgamma but only a 20% reduction in ligand stimulation of the S112A allele. Thus, the mutation at position 112 reduces the negative effect of TPA on PPARgamma -mediated transcription, suggesting that the common growth factor-mediated phosphorylation may negatively modulate PPARgamma activity. To specifically examine the role of MAP kinase, we also examined the effects of an activated allele of MEK on PPARgamma activity. Activated MEK suppressed the transcriptional activity of wild-type PPARgamma but had only a small effect on the S112A mutant PPARgamma (Fig. 3B). These data add further support to the role of a MAP kinase in mediating this suppression.


Fig. 3. Effects of TPA and activated MEK on the transcriptional activity of wild-type and S112A PPARgamma . (A) Rat-IR cells were transfected with a reporter gene PPRE3-luciferase (9) (2 µg) along with PPARgamma and RXRalpha expression vectors (1 µg of each) (SV-sport-PPARgamma and SV-sport-RXRalpha ) (8). After 12 hours, cells were washed and re-fed with DMEM medium containing 0.5% bovine serum albumin. After 24 hours, cells were stimulated with pioglitazone (Pio) (5 µM), TPA (100 ng/ml), or both, or left unstimulated (-). Cells were harvested 18 hours later, and luciferase activity was assayed according to standard procedures. (B) Cells were transfected with PPRE3-luciferase, PPARgamma , and RXRalpha expression vectors along with an expression vector containing activated MEK-1 (A-MEK) (2 µg) (28). Cells were treated with or without pioglitazone, and luciferase activities were measured. Transfection efficiency was monitored and normalized by cotransfecting cells with 2 µg of pCH110 (Pharmacia) vector for beta -galactosidase. Error bars represent the standard deviation. [View Larger Versions of these Images (39K GIF file)]

To assess the effects of the S112A mutation on differentiation, we expressed this mutant allele or the wild-type PPARgamma in NIH 3T3 cells with retroviral vectors. Differentiation was assessed in the differentiation medium containing serum, insulin, or various amounts of pioglitazone. These cells have been used extensively to investigate the role of PPARgamma and C/EBPs in adipogenesis (10, 11, 12, 20). Similar amounts of both wild-type and mutant PPARgamma mRNAs and proteins were expressed in these cells (Fig. 4A). However, a large increase in differentiation was observed in cells expressing the S112A allele as revealed by lipid accumulation (Fig. 4B) or expression of the differentiation-linked mRNAs adipsin and aP2 (Fig. 4C). The dose-response curve for the differentiation response to pioglitazone was shifted 10- to 100-fold in these two assays. Expression of adipsin and aP2 mRNAs was observed in cells expressing the S112A mutant without the addition of exogenous ligand, whereas these RNAs were not observed in the wild-type cells (Fig. 4C). The time course of differentiation in the presence of 5 µM pioglitazone was followed by glycerol accumulation (Fig. 4D). Cells containing the S112A allele differentiated 2 to 4 days before cells bearing the wild-type allele.


Fig. 4. Adipocyte differentiation induced by wild-type and S112A PPARgamma in NIH 3T3 cells. (A) Expression of wild-type and mutant PPARgamma in NIH 3T3 cells. The pBabe retroviral vector (29) was used to express wild-type and S112A mutant PPARgamma in NIH 3T3 cells. Viral infection and cell selections were done as described (10). Expression of viral PPARgamma mRNA (top two panels) and protein (bottom panel) is shown. No endogenous PPARgamma mRNA or protein was detected in NIH 3T3 cells (17). EtBr, ethidium bromide-stained gel. (B) Adipose differentiation of NIH 3T3 cells expressing wild-type or mutant PPARgamma with various doses of pioglitazone. Differentiation conditions were essentially as described (10). Ten days after induction, dishes were stained with Oil-Red-O and photographed. (C) Total RNA was isolated from NIH 3T3 cells expressing wild-type or mutant PPARgamma that had been treated with the indicated concentration of pioglitazone and probed with the adipocyte-specific cDNAs adipsin (Adp.) and aP2. Equal loading of RNA was ensured by ethidium bromide staining (bottom panel). (D) Triglyceride accumulation in cells expressing wild-type or mutant PPARgamma . NIH 3T3 cells expressing wild-type or mutant PPARgamma were induced to differentiate with insulin (5 µg/ml), 1 µM dexamethasone, and 5 µM of pioglitazone in DMEM containing fetal bovine serum (10%). Total triglyceride content of the cells was measured with a triglyceride (GPO-Trinder) kit (Sigma) at various times during the differentiation process. The triglyceride content per milligram of protein for each time point was plotted. [View Larger Versions of these Images (164K GIF file)]

Finally, the ability of a mitogen to interfere with differentiation driven by wild-type and mutant PPARgamma was examined. TPA blocks adipogenesis of standard preadipocyte cell lines (2). TPA inhibited (50 to 80%) the expression of three differentiation-linked genes in cells expressing wild-type PPARgamma : aP2, adipsin, and lipoprotein lipase (LPL) (Fig. 5). In contrast, morphological adipogenesis (17) and expression of the differentiation-linked genes in cells expressing mutant PPARgamma were basically unaffected by the presence of TPA throughout the differentiation protocol. These results demonstrate that mutation of Ser112 of PPARgamma strongly suppresses the ability of TPA to inhibit adipogenesis.


Fig. 5. Effects of TPA on adipocyte differentiation in NIH 3T3 cells expressing wild-type and S112A mutant. (A) NIH 3T3 cells expressing wild-type and mutant PPARgamma were induced to differentiate with insulin (5 µg/ml), dexamethasone (1 µM), and pioglitazone (5 µM) as described in Fig. 4D. TPA (100 ng/ml) was added to half of the dishes at the onset of the induction. Ten days after induction, total RNAs were isolated and blotted with aP2, adipsin (Adp.), or LPL. RNA loading was controlled with EtBr staining. (B) Quantitation of mRNA. The amount of mRNA was quantitated by densitometry scanning (LKB Pharmacia). One representative experiment is shown. The expression level of these three genes in NIH 3T3 cells expressing the PPARgamma mutant was defined as 100%. [View Larger Versions of these Images (78K GIF file)]

The ability to balance cell growth and differentiation is critical in the development of multicellular organisms. The data shown here illustrate a rather clear and simple mechanism for interaction between these two processes; MAP kinase, a central regulator of cell growth, modifies PPARgamma in a way that significantly reduces its transcriptional activity and ability to promote adipogenesis. MAP kinase may be particularly suitable for this purpose because, among the signal transduction machinery linked to the cell cycle, MAP kinase can enter the nucleus to modify transcription factors (21). It is interesting to note that MAP kinase has been implicated in the phosphorylation of another nuclear receptor, the estrogen receptor, although this correlates with an increase in transcriptional activity (22).

These data may have implications for insulin resistance as well as for adipogenesis. The demonstration that PPARgamma is the high-affinity receptor for the thiazolidinedione class of insulin-sensitizing drugs suggests that this receptor is involved in systemic insulin action. This conclusion would imply that peptides or hormones that cause MAP kinase-mediated Ser112 modification of PPARgamma could cause resistance to insulin. In this regard, it is notable that TPA and insulin itself can cause this modification of endogenous PPARgamma (17).

Finally, it will be important to determine the mechanisms by which phosphorylation of Ser112 reduces the activity of PPARgamma . This could occur by direct interference with the binding of ligands, although the region around Ser112 is not near the ligand-binding domain, which resides at the COOH-terminus. Alternatively, this modification could control interactions between PPARgamma and co-repressors or coactivators that have been described to interact with many members of the nuclear receptor family (23). Whether such interactions and their regulation by MAP kinase-mediated phosphorylation contribute to PPARgamma function in adipogenesis in vivo remains to be studied.

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23 September 1996; accepted 4 November 1996


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PNAS 105, 1943-1948
   Abstract »    Full Text »    PDF »
Parvin- Inhibits Breast Cancer Tumorigenicity and Promotes CDK9-Mediated Peroxisome Proliferator-Activated Receptor Gamma 1 Phosphorylation.
C. N. Johnstone, P. S. Mongroo, A. S. Rich, M. Schupp, M. J. Bowser, A. S. deLemos, J. W. Tobias, Y. Liu, G. E. Hannigan, and A. K. Rustgi (2008)
Mol. Cell. Biol. 28, 687-704
   Abstract »    Full Text »    PDF »
Phosphorylation of Steroidogenic Factor 1 Is Mediated by Cyclin-Dependent Kinase 7.
A. E. Lewis, M. Rusten, E. A. Hoivik, E. L. Vikse, M. L. Hansson, A. E. Wallberg, and M. Bakke (2008)
Mol. Endocrinol. 22, 91-104
   Abstract »    Full Text »    PDF »
Evodiamine Improves Diet-Induced Obesity in a Uncoupling Protein-1-Independent Manner: Involvement of Antiadipogenic Mechanism and Extracellularly Regulated Kinase/Mitogen-Activated Protein Kinase Signaling.
T. Wang, Y. Wang, Y. Kontani, Y. Kobayashi, Y. Sato, N. Mori, and H. Yamashita (2008)
Endocrinology 149, 358-366
   Abstract »    Full Text »    PDF »
Genetic and Pharmacological Inhibition of Rho-associated Kinase II Enhances Adipogenesis.
M. Noguchi, K. Hosoda, J. Fujikura, M. Fujimoto, H. Iwakura, T. Tomita, T. Ishii, N. Arai, M. Hirata, K. Ebihara, et al. (2007)
J. Biol. Chem. 282, 29574-29583
   Abstract »    Full Text »    PDF »
Hyperglycemia Enhances Adipogenic Induction of Lipid Accumulation: Involvement of Extracellular Signal-Regulated Protein Kinase 1/2, Phosphoinositide 3-Kinase/Akt, and Peroxisome Proliferator-Activated Receptor {gamma} Signaling.
C. C. Chuang, R. S. Yang, K. S. Tsai, F. M. Ho, and S. H. Liu (2007)
Endocrinology 148, 4267-4275
   Abstract »    Full Text »    PDF »
Reversine increases the plasticity of lineage-committed mammalian cells.
S. Chen, S. Takanashi, Q. Zhang, W. Xiong, S. Zhu, E. C. Peters, S. Ding, and P. G. Schultz (2007)
PNAS 104, 10482-10487
   Abstract »    Full Text »    PDF »
Statins Activate Peroxisome Proliferator-Activated Receptor {gamma} Through Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase-Dependent Cyclooxygenase-2 Expression in Macrophages.
M. Yano, T. Matsumura, T. Senokuchi, N. Ishii, Y. Murata, K. Taketa, H. Motoshima, T. Taguchi, K. Sonoda, D. Kukidome, et al. (2007)
Circ. Res. 100, 1442-1451
   Abstract »    Full Text »    PDF »
Pref-1 (Preadipocyte Factor 1) Activates the MEK/Extracellular Signal-Regulated Kinase Pathway To Inhibit Adipocyte Differentiation.
K.-A. Kim, J.-H. Kim, Y. Wang, and H. S. Sul (2007)
Mol. Cell. Biol. 27, 2294-2308
   Abstract »    Full Text »    PDF »
Nitric oxide activation of peroxisome proliferator-activated receptor gamma through a p38 MAPK signaling pathway.
A. Ptasinska, S. Wang, J. Zhang, R. A. Wesley, and R. L. Danner (2007)
FASEB J 21, 950-961
   Abstract »    Full Text »    PDF »
Interaction with MEK Causes Nuclear Export and Downregulation of Peroxisome Proliferator-Activated Receptor {gamma}.
E. Burgermeister, D. Chuderland, T. Hanoch, M. Meyer, M. Liscovitch, and R. Seger (2007)
Mol. Cell. Biol. 27, 803-817
   Abstract »    Full Text »    PDF »
Oncostatin M Inhibits Adipogenesis through the RAS/ERK and STAT5 Signaling Pathways.
Y. Miyaoka, M. Tanaka, T. Naiki, and A. Miyajima (2006)
J. Biol. Chem. 281, 37913-37920
   Abstract »    Full Text »    PDF »
Preadipocytes Mediate Lipopolysaccharide-Induced Inflammation and Insulin Resistance in Primary Cultures of Newly Differentiated Human Adipocytes.
S. Chung, K. LaPoint, K. Martinez, A. Kennedy, M. Boysen Sandberg, and M. K. McIntosh (2006)
Endocrinology 147, 5340-5351
   Abstract »    Full Text »    PDF »
ERK Signaling Is a Molecular Switch Integrating Opposing Inputs from B Cell Receptor and T Cell Cytokines to Control TLR4-Driven Plasma Cell Differentiation.
L. Rui, J. I. Healy, J. Blasioli, and C. C. Goodnow (2006)
J. Immunol. 177, 5337-5346
   Abstract »    Full Text »    PDF »
Porcine peroxisome proliferator-activated receptor {gamma} induces transdifferentiation of myocytes into adipocytes.
Y. H. Yu, B. H. Liu, H. J. Mersmann, and S. T. Ding (2006)
J Anim Sci 84, 2655-2665
   Abstract »    Full Text »    PDF »
Antitumorigenic Effect of Wnt 7a and Fzd 9 in Non-small Cell Lung Cancer Cells Is Mediated through ERK-5-dependent Activation of Peroxisome Proliferator-activated Receptor {gamma}.
R. A. Winn, M. Van Scoyk, M. Hammond, K. Rodriguez, J. T. Crossno Jr., L. E. Heasley, and R. A. Nemenoff (2006)
J. Biol. Chem. 281, 26943-26950
   Abstract »    Full Text »    PDF »
Peroxisome Proliferator-activated Receptor-{gamma}1 Is Dephosphorylated and Degraded during BAY 11-7085-induced Synovial Fibroblast Apoptosis.
B. Relic, V. Benoit, N. Franchimont, M.-J. Kaiser, J.-P. Hauzeur, P. Gillet, M.-P. Merville, V. Bours, and M. G. Malaise (2006)
J. Biol. Chem. 281, 22597-22604
   Abstract »    Full Text »    PDF »
Significance of anti-inflammatory effects of PPAR{gamma} agonists?.
G Rogler (2006)
Gut 55, 1067-1069
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Berberine, a Natural Plant Product, Activates AMP-Activated Protein Kinase With Beneficial Metabolic Effects in Diabetic and Insulin-Resistant States..
Y. S. Lee, W. S. Kim, K. H. Kim, M. J. Yoon, H. J. Cho, Y. Shen, J.-M. Ye, C. H. Lee, W. K. Oh, C. T. Kim, et al. (2006)
Diabetes 55, 2256-2264
   Abstract »    Full Text »    PDF »
Ectodomain Shedding of Preadipocyte Factor 1 (Pref-1) by Tumor Necrosis Factor Alpha Converting Enzyme (TACE) and Inhibition of Adipocyte Differentiation..
Y. Wang and H. S. Sul (2006)
Mol. Cell. Biol. 26, 5421-5435
   Abstract »    Full Text »    PDF »
Peroxisome Proliferator-Activated Receptor {gamma} Recruits the Positive Transcription Elongation Factor b Complex to Activate Transcription and Promote Adipogenesis.
I. Iankova, R. K. Petersen, J.-S. Annicotte, C. Chavey, J. B. Hansen, I. Kratchmarova, D. Sarruf, M. Benkirane, K. Kristiansen, and L. Fajas (2006)
Mol. Endocrinol. 20, 1494-1505
   Abstract »    Full Text »    PDF »
Upregulation of gene encoding adipogenic transcriptional factors C/EBP{alpha} and PPAR{gamma}2 in denervated muscle.
A. Wagatsuma (2006)
Exp Physiol 91, 747-753
   Abstract »    Full Text »    PDF »
The Peroxisome Proliferator-Activated Receptor N-Terminal Domain Controls Isotype-Selective Gene Expression and Adipogenesis.
S. Hummasti and P. Tontonoz (2006)
Mol. Endocrinol. 20, 1261-1275
   Abstract »    Full Text »    PDF »
Attenuation of Peroxisome Proliferator-activated Receptor {gamma} (PPAR{gamma}) Mediates Gastrin-stimulated Colorectal Cancer Cell Proliferation.
A. J. Chang, D. H. Song, and M. M. Wolfe (2006)
J. Biol. Chem. 281, 14700-14710
   Abstract »    Full Text »    PDF »
Antagonistic Effects of Oxidized Low Density Lipoprotein and {alpha}-Tocopherol on CD36 Scavenger Receptor Expression in Monocytes: INVOLVEMENT OF PROTEIN KINASE B AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-{gamma}.
A. Munteanu, M. Taddei, I. Tamburini, E. Bergamini, A. Azzi, and J.-M. Zingg (2006)
J. Biol. Chem. 281, 6489-6497
   Abstract »    Full Text »    PDF »
Regulation of Nuclear Translocation of HDAC3 by I{kappa}B{alpha} Is Required for Tumor Necrosis Factor Inhibition of Peroxisome Proliferator-activated Receptor {gamma} Function.
Z. Gao, Q. He, B. Peng, P. J. Chiao, and J. Ye (2006)
J. Biol. Chem. 281, 4540-4547
   Abstract »    Full Text »    PDF »
Effects of luteinizing hormone on peroxisome proliferator-activated receptor {gamma} in the rat ovary before and after the gonadotropin surge.
J. Banerjee and C. M Komar (2006)
Reproduction 131, 93-101
   Abstract »    Full Text »    PDF »
Cyclin D3 Promotes Adipogenesis through Activation of Peroxisome Proliferator-Activated Receptor {gamma}.
D. A. Sarruf, I. Iankova, A. Abella, S. Assou, S. Miard, and L. Fajas (2005)
Mol. Cell. Biol. 25, 9985-9995
   Abstract »    Full Text »    PDF »
Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans.
S. Cinti, G. Mitchell, G. Barbatelli, I. Murano, E. Ceresi, E. Faloia, S. Wang, M. Fortier, A. S. Greenberg, and M. S. Obin (2005)
J. Lipid Res. 46, 2347-2355
   Abstract »    Full Text »    PDF »
Tungstate Decreases Weight Gain and Adiposity in Obese Rats through Increased Thermogenesis and Lipid Oxidation.
M. Claret, H. Corominola, I. Canals, J. Saura, S. Barcelo-Batllori, J. J. Guinovart, and R. Gomis (2005)
Endocrinology 146, 4362-4369
   Abstract »    Full Text »    PDF »
Activation of Mitogen-Activated Protein Kinases by Peroxisome Proliferator-Activated Receptor Ligands: An Example of Nongenomic Signaling.
O. S. Gardner, B. J. Dewar, and L. M. Graves (2005)
Mol. Pharmacol. 68, 933-941
   Abstract »    Full Text »    PDF »
The Molecular Scaffold Kinase Suppressor of Ras 1 (KSR1) Regulates Adipogenesis.
R. L. Kortum, D. L. Costanzo, J. Haferbier, S. J. Schreiner, G. L. Razidlo, M.-H. Wu, D. J. Volle, T. Mori, H. Sakaue, N. V. Chaika, et al. (2005)
Mol. Cell. Biol. 25, 7592-7604
   Abstract »    Full Text »    PDF »
Leptin Modulates both Resorption and Formation while Preventing Disuse-Induced Bone Loss in Tail-Suspended Female Rats.
A. Martin, R. de Vittoris, V. David, R. Moraes, M. Begeot, M.-H. Lafage-Proust, C. Alexandre, L. Vico, and T. Thomas (2005)
Endocrinology 146, 3652-3659
   Abstract »    Full Text »    PDF »
Dysregulation of the Peroxisome Proliferator-Activated Receptor Target Genes by XPD Mutations.
E. Compe, P. Drane, C. Laurent, K. Diderich, C. Braun, J. H. J. Hoeijmakers, and J.-M. Egly (2005)
Mol. Cell. Biol. 25, 6065-6076
   Abstract »    Full Text »    PDF »
Peroxisome Proliferator-Activated Receptor-{gamma} and Retinoid X Receptor Signaling Regulate Fatty Acid Uptake by Primary Human Placental Trophoblasts.
W. T. Schaiff, I. Bildirici, M. Cheong, P. L. Chern, D. M. Nelson, and Y. Sadovsky (2005)
J. Clin. Endocrinol. Metab. 90, 4267-4275
   Abstract »    Full Text »    PDF »
Regulation of Macrophage Cholesterol Efflux through Hydroxymethylglutaryl-CoA Reductase Inhibition: A ROLE FOR RhoA IN ABCA1-MEDIATED CHOLESTEROL EFFLUX.
C. A. Argmann, J. Y. Edwards, C. G. Sawyez, C. H. O'Neil, R. A. Hegele, J. G. Pickering, and M. W. Huff (2005)
J. Biol. Chem. 280, 22212-22221
   Abstract »    Full Text »    PDF »
Role of MLK3 in the Regulation of Mitogen-Activated Protein Kinase Signaling Cascades.
D. Brancho, J.-J. Ventura, A. Jaeschke, B. Doran, R. A. Flavell, and R. J. Davis (2005)
Mol. Cell. Biol. 25, 3670-3681
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A Novel Ring-Substituted Diindolylmethane,1,1-Bis[3'-(5-Methoxyindolyl)]-1-(p-t-Butylphenyl) Methane, Inhibits Extracellular Signal-Regulated Kinase Activation and Induces Apoptosis in Acute Myelogenous Leukemia.
R. Contractor, I. J. Samudio, Z. Estrov, D. Harris, J. A. McCubrey, S. H. Safe, M. Andreeff, and M. Konopleva (2005)
Cancer Res. 65, 2890-2898
   Abstract »    Full Text »    PDF »
Role of Kruppel-like Factor 15 (KLF15) in Transcriptional Regulation of Adipogenesis.
T. Mori, H. Sakaue, H. Iguchi, H. Gomi, Y. Okada, Y. Takashima, K. Nakamura, T. Nakamura, T. Yamauchi, N. Kubota, et al. (2005)
J. Biol. Chem. 280, 12867-12875
   Abstract »    Full Text »    PDF »
Differential Effects of Phthalates on the Testis and the Liver.
N. Bhattacharya, J. M. Dufour, M.-N. Vo, J. Okita, R. Okita, and K. H. Kim (2005)
Biol Reprod 72, 745-754
   Abstract »    Full Text »    PDF »
c-Jun N-Terminal Kinase Contributes to Aberrant Retinoid Signaling in Lung Cancer Cells by Phosphorylating and Inducing Proteasomal Degradation of Retinoic Acid Receptor {alpha}.
H. Srinivas, D. M. Juroske, S. Kalyankrishna, D. D. Cody, R. E. Price, X.-C. Xu, R. Narayanan, N. L. Weigel, and J. M. Kurie (2005)
Mol. Cell. Biol. 25, 1054-1069
   Abstract »    Full Text »    PDF »
The Extracellular Signal-Regulated Kinase Isoform ERK1 Is Specifically Required for In Vitro and In Vivo Adipogenesis.
F. Bost, M. Aouadi, L. Caron, P. Even, N. Belmonte, M. Prot, C. Dani, P. Hofman, G. Pages, J. Pouyssegur, et al. (2005)
Diabetes 54, 402-411
   Abstract »    Full Text »    PDF »
Resistin expression in 3T3-L1 adipocytes is reduced by arachidonic acid.
F. Haugen, N. Zahid, K. T. Dalen, K. Hollung, H. I. Nebb, and C. A. Drevon (2005)
J. Lipid Res. 46, 143-153
   Abstract »    Full Text »    PDF »
Peroxisome Proliferator-Activated Receptor-{gamma} Calls for Activation in Moderation: Lessons from Genetics and Pharmacology.
C. Knouff and J. Auwerx (2004)
Endocr. Rev. 25, 899-918
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Fad24, a mammalian homolog of Noc3p, is a positive regulator in adipocyte differentiation.
K. Tominaga, Y. Johmura, M. Nishizuka, and M. Imagawa (2004)
J. Cell Sci. 117, 6217-6226
   Abstract »    Full Text »    PDF »
Differential Peroxisome Proliferator-Activated Receptor-{gamma} Isoform Expression and Agonist Effects in Normal and Malignant Prostate Cells.
V. Subbarayan, A. L. Sabichi, J. Kim, N. Llansa, C. J. Logothetis, S. M. Lippman, and D. G. Menter (2004)
Cancer Epidemiol. Biomarkers Prev. 13, 1710-1716
   Abstract »    Full Text »    PDF »
The transactivating function of peroxisome proliferator-activated receptor {gamma} is negatively regulated by SUMO conjugation in the amino-terminal domain.
D. Yamashita, T. Yamaguchi, M. Shimizu, N. Nakata, F. Hirose, and T. Osumi (2004)
Genes Cells 9, 1017-1029
   Abstract »    Full Text »    PDF »
The Hinge-Helix 1 Region of Peroxisome Proliferator-Activated Receptor {gamma}1 (PPAR{gamma}1) Mediates Interaction with Extracellular Signal-Regulated Kinase 5 and PPAR{gamma}1 Transcriptional Activation: Involvement in Flow-Induced PPAR{gamma} Activation in Endothelial Cells.
M. Akaike, W. Che, N.-L. Marmarosh, S. Ohta, M. Osawa, B. Ding, B. C. Berk, C. Yan, and J.-i. Abe (2004)
Mol. Cell. Biol. 24, 8691-8704
   Abstract »    Full Text »    PDF »
Haploid Inactivation of the Amplified-in-Breast Cancer 3 Coactivator Reduces the Inhibitory Effect of Peroxisome Proliferator-Activated Receptor {gamma} and Retinoid X Receptor on Cell Proliferation and Accelerates Polyoma Middle-T Antigen-Induced Mammary Tumorigenesis in Mice.
H. Zhang, S.-Q. Kuang, L. Liao, S. Zhou, and J. Xu (2004)
Cancer Res. 64, 7169-7177
   Abstract »    Full Text »    PDF »
Role of MAPK Phosphatase-1 (MKP-1) in Adipocyte Differentiation.
H. Sakaue, W. Ogawa, T. Nakamura, T. Mori, K. Nakamura, and M. Kasuga (2004)
J. Biol. Chem. 279, 39951-39957
   Abstract »    Full Text »    PDF »
Advanced glycation end products potentiate the stimulatory effect of glucose on macrophage lipoprotein lipase expression.
M.-C. Beauchamp, S.-E. Michaud, L. Li, M. R. Sartippour, and G. Renier (2004)
J. Lipid Res. 45, 1749-1757
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Inhibition of adipocyte differentiation by mechanical stretching through ERK-mediated downregulation of PPAR{gamma}2.
Y. Tanabe, M. Koga, M. Saito, Y. Matsunaga, and K. Nakayama (2004)
J. Cell Sci. 117, 3605-3614
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Transcriptional Activity of Peroxisome Proliferator-activated Receptor {gamma} Is Modulated by SUMO-1 Modification.
T. Ohshima, H. Koga, and K. Shimotohno (2004)
J. Biol. Chem. 279, 29551-29557
   Abstract »    Full Text »    PDF »
Peroxisome Proliferator Activated Receptors {alpha} and {gamma} Require Zinc for Their Anti-inflammatory Properties in Porcine Vascular Endothelial Cells.
G. Reiterer, M. Toborek, and B. Hennig (2004)
J. Nutr. 134, 1711-1715
   Abstract »    Full Text »
Conjugated Linoleic Acid Induces Human Adipocyte Delipidation: AUTOCRINE/PARACRINE REGULATION OF MEK/ERK SIGNALING BY ADIPOCYTOKINES.
J. M. Brown, M. S. Boysen, S. Chung, O. Fabiyi, R. F. Morrison, S. Mandrup, and M. K. McIntosh (2004)
J. Biol. Chem. 279, 26735-26747
   Abstract »    Full Text »    PDF »
Sequestration of Thermogenic Transcription Factors in the Cytoplasm during Development of Brown Adipose Tissue.
J. S. Rim, B. Xue, B. Gawronska-Kozak, and L. P. Kozak (2004)
J. Biol. Chem. 279, 25916-25926
   Abstract »    Full Text »    PDF »
Extracellular Signal-Regulated Kinase Induces the Megakaryocyte GPIIb/CD41 Gene through MafB/Kreisler.
J. R. Sevinsky, A. M. Whalen, and N. G. Ahn (2004)
Mol. Cell. Biol. 24, 4534-4545
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Tumor necrosis factor-{alpha} inhibits peroxisome proliferator-activated receptor {gamma} activity at a posttranslational level in hepatic stellate cells.
C. K. Sung, H. She, S. Xiong, and H. Tsukamoto (2004)
Am J Physiol Gastrointest Liver Physiol 286, G722-G729
   Abstract »    Full Text »    PDF »
Inhibition of Adipogenesis by Ghrelin.
W. Zhang, L. Zhao, T. R. Lin, B. Chai, Y. Fan, I. Gantz, and M. W. Mulholland (2004)
Mol. Biol. Cell 15, 2484-2491
   Abstract »    Full Text »    PDF »
Adipogenesis: Usefulness of in vitro and in vivo experimental models.
J. Novakofski (2004)
J Anim Sci 82, 905-915
   Abstract »    Full Text »    PDF »
Expression of NAG-1, a Transforming Growth Factor-{beta} Superfamily Member, by Troglitazone Requires the Early Growth Response Gene EGR-1.
S. J. Baek, J.-S. Kim, J. B. Nixon, R. P. DiAugustine, and T. E. Eling (2004)
J. Biol. Chem. 279, 6883-6892
   Abstract »    Full Text »    PDF »
Controlling muscle mitochondrial content.
C. D. Moyes (2003)
J. Exp. Biol. 206, 4385-4391
   Abstract »    Full Text »    PDF »
Arachidonic acid-dependent inhibition of adipocyte differentiation requires PKA activity and is associated with sustained expression of cyclooxygenases.
R. K. Petersen, C. Jorgensen, A. C. Rustan, L. Froyland, K. Muller-Decker, G. Furstenberger, R. K. Berge, K. Kristiansen, and L. Madsen (2003)
J. Lipid Res. 44, 2320-2330
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The Divergent Orphan Nuclear Receptor ODR-7 Regulates Olfactory Neuron Gene Expression via Multiple Mechanisms in Caenorhabditis elegans.
M. E. Colosimo, S. Tran, and P. Sengupta (2003)
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Deregulated MAPK Activity Prevents Adipocyte Differentiation of Fibroblasts Lacking the Retinoblastoma Protein.
J. B. Hansen, R. K. Petersen, C. Jorgensen, and K. Kristiansen (2002)
J. Biol. Chem. 277, 26335-26339
   Abstract »    Full Text »    PDF »


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Science. ISSN 0036-8075 (print), 1095-9203 (online)