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1 and Negatively Regulates Its Transcriptional Activity
Department of Cell Biology (H.S.C., T.L.), Department of Molecular Biology (S.R.T.), Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, Michigan 48105; and the Department of Biological Chemistry, University of Michigan Medical School (T.L.), Ann Arbor, Michigan 48109
Address all correspondence and requests for reprints to: Dr. Todd Leff, Parke-Davis, Department of Cell Biology, 2800 Plymouth Road, Ann Arbor, Michigan 48105. E-mail: todd.leff{at}aa.wl.com
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(PPAR)
transcription factor plays a pivotal role in adipocyte differentiation
and metabolic regulation. The transcriptional activity of PPAR is
positively modulated by ligand binding and negatively regulated by
phosphorylation mediated by the MEK/ERK signaling pathway. The
phosphorylation of mouse PPAR1 at Ser82 by ERK causes a
decrease in both basal and ligand-dependent transcriptional activity.
In this report we examined the ability of other mitogen-activated
protein kinase family members to phosphorylate PPAR1. We demonstrate
that in vitro, PPAR1 is efficiently phosphorylated by
JNK/SAPK (c-Jun N-terminal kinase or stress-activated protein kinase)
but only weakly phosphorylated by p38. In transfected 293T cells,
PPAR1 is phosphorylated at Ser82 in response to known
JNK activators such as UV irradiation and anisomycin treatment. This
phosphorylation is not blocked by either the specific MEK inhibitor
PD98059 or the p38 inhibitor SB203580, indicating that it is
independent of the MEK/ERK and p38 signaling pathways. Finally, in
transient transfection reporter assays, activation of JNK by anisomycin
or by overexpression of MKK4 (the upstream JNK kinase) decreased
ligand-dependent PPAR1 transcriptional activity. These results
suggest that the activation of the JNK/SAPK pathway by extracellular
signals, perhaps by inflammatory cytokines such as tumor necrosis
factor-
, would result in a reduction of PPAR transcriptional
activity and reduce the effects of PPAR ligands. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, , and
) differ in their tissue distribution and ligand specificity (for a
review see Ref. 6). PPAR is present in heart, kidney, and liver and
appears to primarily regulate genes involved in lipid and lipoprotein
metabolism, whereas PPAR expression is ubiquitous, and its
physiological role is unclear. PPAR is expressed predominantly in
adipose tissue, with lower levels in muscle and liver (7, 8). Although
the physiological role of PPAR has not been clearly determined, it
appears to be an important transcriptional regulator of genes involved
in glucose and lipid metabolism.
A central role for PPAR in metabolic regulation was demonstrated by
the observation that antidiabetic drugs known as the thiazolidinediones
(TZDs) were high affinity ligands of PPAR (9). TZDs have profound
effects on glucose metabolism in diabetic subjects and appear to act
primarily through PPAR, as indicated by a correlation between the
antidiabetic potency of TZDs and receptor affinity (10). In addition, a
compound (LG268) that specifically binds to RXR, the heterodimeric
partner of PPAR, has a similar anti-diabetic effect (11). Although
many of the details are not clearly understood, a model has emerged in
which activated PPAR modulates the expression of genes involved in
glucose and lipid metabolism. Activation of these PPAR target genes
would lead directly or indirectly to an improvement in the metabolic
defects associated with diabetes (12). This model predicts that
endogenous regulators of PPAR activity would be key components of
the general system that regulates metabolism and energy balance.
In addition to being regulated by ligand binding, PPAR activity is
modulated by phosphorylation. Previously, we and others have shown that
PPAR is phosphorylated by a member of the mitogen-activated protein
(MAP) kinase family, extracellular signal-regulated protein kinase
(ERK), and that phosphorylated PPAR has significantly reduced
transcriptional activity compared with that of the unphosphorylated
version (13, 14, 15). Thus, agents that cause an increase in PPAR
phosphorylation may reduce sensitivity to PPAR ligands such as TZDs
and may even contribute to the development of insulin resistance.
MAP kinases (MAPKs) are a large family of Ser/Thr kinases that are
regulated by extracellular stimuli, including growth factors, mitogens,
and cellular stress (16, 17). In addition to ERK1 and ERK2, which are
activated by growth factors via the Ras/Raf/MEK pathway, there are
three additional MAPK family members that are activated primarily by
stress stimuli: JNK (also termed SAPK) (18, 19, 20), p38 (also termed CSBP)
(21, 22), and BMK1 (also termed ERK5) (23). All of the MAPK family
members display distinct, yet overlapping, substrate recognition
specificity. Because some substrates can be phosphorylated by more than
one MAPK signaling pathway, we sought to investigate whether other
MAPKs could phosphorylate PPAR1. In the current study, we
demonstrate that JNK phosphorylates PPAR1 on Ser82, the
same site phosphorylated by ERK, and that in vivo,
activation of JNK causes a phosphorylation-dependent decrease in
PPAR1 transcriptional activity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In vitro phosphorylation assay
Construction of mutant PPAR1 (Ser82Ala) was
described previously (13). Both the wild-type and the mutant mouse
PPAR1 were in vitro translated using rabbit reticulocyte
lysates in the presence of [35S]Met. One tenth of the
in vitro translated proteins were then incubated with either
activated ERK2 (New England Biolabs, Inc., Beverley, MA),
the activated ß-form of rat JNK (Stratagene, La Jolla,
CA), or activated Xenopus MalE-Mpk2/p38/RK (Upstate Biotechnology, Inc., Lake Placid, NY) as recommended by the
manufacturers. Incubation reactions contained 10 µM cold
ATP and 1 x MAPK buffer (25 mM HEPES, pH 7.5, and 10
mM magnesium acetate). Proteins were resolved in 8
M urea-10% acrylamide gel (100:1,
acrylamide-bisacrylamide) (15) that can separate the phosphorylated
form of PPAR from unphosphorylated PPAR. The gel was dried and
exposed for autoradiography. Bacterially expressed myelin basic protein
(MBP) and c-Jun were used as kinase substrates in control reactions
(MBP for ERK2 and p38, and c-Jun for JNK) containing 10
µM [-32P]ATP, 25 mM HEPES
(pH 7.5), and 10 mM magnesium acetate.
In vivo phosphorylation of PPAR
293T cells were maintained in DMEM containing 10% FCS
(Life Technologies, Inc.). Cells were transfected with
mouse full-length wild-type PPAR1 or mutant PPAR1
(Ser82Ala) using lipofectamine (Life Technologies, Inc.). Cells were harvested in HNTG lysis buffer
[50 mM HEPES (pH 7.5), 150 mM NaCl, 1% Triton
X-100, 10% glycerol, 1 mM EDTA, 100 mM NaF,
and complete protease inhibitors, used according to the manufacturer’s
directions; Sigma Chemical Co., St. Louis, MO]. Proteins
were resolved in 8 M urea-10% acrylamide (100:1,
acrylamide-bisacrylamide) gel (15). PPAR protein was visualized by
blotting with a polyclonal anti-PPAR antibody raised against
recombinant mouse PPAR1 (13). Immunological detection of activated
kinases by Western blot analysis was carried out using anti-ACTIVE MAPK
(Promega Corp., Madison, WI), anti-phospho-SAPK/JNK
(New England Biolabs, Inc.), and phospho-specific p38 MAPK
(New England Biolabs, Inc.) polyclonal antibodies.
Transient reporter assays
The reporter construct used in the transient transfections
contained three copies of the PPRE site from the aP2 enhancer (ARE6)
(24) inserted upstream of a minimal thymidine kinase (TK) promoter in
the pGL3 (Promega Corp.) luciferase vector. 293T cells
were grown in 10% FCS-DMEM and cotransfected with mouse PPAR1 (200
ng) and mouse RXR (50 ng) expression plasmids, the TK luciferase
reporter plasmid (200 ng), and an internal reference plasmid pCMV (CMV,
cytomegalovirus) ß-galactosidase (50 ng) using lipofectamine
(Life Technologies, Inc.). In some experiments, 200 ng of
an expression vector producing MKK4 were transfected into cells along
with PPAR1. After transfection, cells were treated for 24 h
with 25 µM BRL 49653 and further treated
with 2 µg/ml anisomycin for the last 6 h or by UV irradiation
(0.1 J in a Stratagene UV Stratalinker 1800) that was
delivered 6 h before harvesting cells. Luciferase and
ß-galactosidase activities were determined using a luciferase assay
(Promega Corp.) and Galacto-light system (Tropix, Inc.,
Bedford, MA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 in vitro1 is phosphorylated at
Ser82 by the MAPK family member ERK2 (13). To determine
whether PPAR1 can be phosphorylated by other MAPK family members,
such as JNK and p38, [35S]Met-labeled wild-type and
mutant versions of PPAR1 were synthesized by in vitro
translation and incubated with the activated forms of various MAPKs.
The phosphorylation state of PPAR1 was then assessed using a gel
shift assay in which phosphorylated PPAR1 migrates more slowly than
the unphosphorylated protein. Both ERK2 and JNK efficiently
phosphorylated PPAR1 (22% and 23% phosphorylation, respectively),
whereas PPAR1 was only weakly phosphorylated by p38 (9% compared
with 4% for the control reaction; Fig. 1a
). The low activity of p38 on PPAR1
was not due to inactive kinase as demonstrated by the phosphorylation
of MBP by the same preparation of p38 (Fig. 1b). Both ERK2 and JNK were
also shown to be active in this control assay. The phosphorylation of
PPAR by ERK2 and JNK was independently confirmed in a direct
in vitro phosphorylation assay using
[-32P]ATP and recombinant PPAR protein purified
from Escherichia coli (data not shown). Taken together,
these results demonstrate that JNK is as active as ERK2 in terms of its
ability to phosphorylate PPAR in vitro.
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phosphorylation in 293T cells1 can be phosphorylated by known
JNK/p38 activators, serum-starved 293T cells transfected with PPAR1
were treated with anisomycin or with UV light. Whole cell extracts were
then prepared, and the phosphorylation state of PPAR1 was assessed
using a gel shift assay. As shown in Fig. 2a, treatment with
anisomycin or UV light caused an increase in PPAR1 phosphorylation
compared to in the untreated control cell extracts (Fig. 2a, lanes 5
and 6, and 7 and 8). To determine whether the MEK/ERK signaling pathway
is involved or contributes to this phosphorylation, cells were
pretreated with PD98059, a specific MEK inhibitor. As shown in Fig. 2a, PD98059 did not block anisomycin-induced PPAR phosphorylation (lane
6), indicating that this phosphorylation was not caused by activation
of the MEK/ERK signaling pathway. However, PD98059 did cause a slight
reduction in UV light-induced PPAR phosphorylation, suggesting
ERK1/2 might contribute to PPAR phosphorylation induced by UV light
(Fig. 2a, lane 8). This interpretation is supported by the control
experiments presented in Fig. 2c. Although anisomycin treatment
specifically activated JNK and p38, UV light treatment caused a slight
increase in ERK2 activation in addition to a strong activation of JNK
and p38. As a control, cells were also treated with TPA, a known
activator of MEK/ERK. As previously reported (15), this treatment
caused a significant increase in PPAR phosphorylation that was
completely blocked by PD98059 (Fig. 2a, lanes 3 and 4).
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1
phosphorylation via the JNK or the p38 signaling pathways. To examine
this question, cells were incubated with either TPA or anisomycin in
the absence or presence of a p38 inhibitor SB203580, which was shown
previously to specifically block p38 kinase activity (29, 30). Cells
were harvested, and the phosphorylation status of PPAR1 was
determined as described above. As demonstrated in Fig. 2b
, PPAR1
phosphorylation induced by either TPA or anisomycin was not altered in
the presence of SB203580. These results suggest that p38 is not
responsible for the phosphorylation of PPAR1 in response to
stress-inducing agents such as anisomycin.
Previously, we have shown that there is a single MAPK phosphorylation
site in the N-terminal region located at Ser82 of mouse
PPAR1 (13). To determine whether Ser82 is also the
residue that is phosphorylated by JNK, 293T cells were transfected with
either wild-type PPAR1 or a mutant form of PPAR1 that contains an
alanine residue substituted for serine at position 82
(Ser82Ala). Transfected cells were treated with TPA or
anisomycin, and the degree of PPAR1 phosphorylation was measured
using the gel shift assay described above. As shown in Fig. 3, both TPA and anisomycin induced an
approximately 5-fold stimulation of wild-type PPAR1 phosphorylation,
but both agents failed to induce the phosphorylation of the
Ser82Ala mutant. These results demonstrate that in
vivo, Ser82 of PPAR1 is the phosphorylation site
for both ERK and JNK.
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-dependent transcriptional
activity1 at Ser82 by ERK has been
shown to significantly decrease its transcriptional activity (13, 14, 15).
To confirm that JNK activation causes a similar decrease in PPAR1
transcriptional activity, a PPAR-dependent transient transcription
assay was performed. PPAR activity was measured using a minimal TK
reporter plasmid containing three copies of the PPAR-binding site
(ARE6) from the aP2 gene promoter (24). 293T cells were transfected
with this reporter (ARE6/TKpGL3) together with PPAR1 and RXR and
treated with either anisomycin or UV light. Because anisomycin is a
general protein synthesis inhibitor, we performed a dose-response and
time-course experiment to identify conditions that did not inhibit
protein synthesis, but still activated JNK. Treatment of 293T cells
with 2 µg/ml anisomycin for up to 7 h did not change
ß-galactosidase expression from a transfected reference plasmid (data
not shown). Transfected cells were allowed to recover overnight in the
presence or absence of the PPAR ligand BRL 49653 and
then treated for 6 h with anisomycin or by exposure to UV light
6 h before harvest. As presented in Fig. 4a, both anisomycin and UV light
treatment decreased ligand-dependent PPAR1 transcriptional activity
by 50% and 40%, respectively. In this system, treatment with UV light
and anisomycin did not affect basal transcriptional activity in the
absence of ligand. These results indicate that PPAR phosphorylation
by the JNK pathway leads to a decrease in ligand-dependent PPAR
transcriptional activity.
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and the reporter plasmid described above
(ARE6/TKpGL3) together with a plasmid expressing MKK4 and assessed
PPAR1-dependent transcriptional activity. In the presence of
overexpressing MKK4, a slight reduction of basal and a dramatic
inhibition of ligand-dependent PPAR1 transcriptional activity was
observed (Fig. 4b). Taken together, these results indicate that JNK
activation leads to decreased PPAR1 activity as a result of
phosphorylation at Ser82 and suggests that physiological
stimuli that activate the JNK pathway could have a negative effect on
the expression of PPAR target genes. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is a key component of the system that regulates energy
metabolism and glucose homeostasis. The primary evidence for this
hypothesis is that activating ligands of PPAR can correct many of
the defects in glucose metabolism that appear with type II diabetes
(12, 34). In the current study we have demonstrated that activation of
JNK negatively regulates PPAR transcriptional activity by
phosphorylation at the same site previously reported to be
phosphorylated by ERK. Taken together with previous studies
demonstrating that ERK can regulate PPAR1, our findings suggest that
PPAR transcriptional activity may be subject to negative regulation
by a variety of signals that activate one or more of the MAPK signaling
pathways.
There are several transcription factors that are known to be
phosphorylated at the same site by different MAPK family members. The
ternary complex transcription factor protein ELK-1 is a target for all
three MAPKs: ERK (35), JNK (36), and p38 (27). There are, however, many
examples of distinct specificities for substrate site recognition by
these kinases. For example, SAP-1 is recognized and phosphorylated by
ERK and p38, but not by JNK (37), whereas the transcription factor
MEF2C is phosphorylated with much higher efficiency by p38 then by JNK
or ERK (38). In the case of PPAR, its activity can be clearly
regulated by at least two branches of the MAPK signaling cascade, ERK
and JNK, which suggests that multiple signals can lead to PPAR
phosphorylation and subsequent reduction in the sensitivity of PPAR
to its cognate ligands.
Although the physiological role of PPAR regulation by
phosphorylation is unclear at this time, it must provide a means for a
variety of physiological signals, acting through MAPK signaling
pathways, to affect the expression of PPAR target genes and thereby
alter metabolism. An interesting possibility that is directly related
to our finding that JNK kinase can phosphorylate PPAR1 is suggested
by the observation that at least in some cells the JNK pathway can be
activated by the inflammatory cytokine tumor necrosis factor-
(TNF) (20, 33). Several studies have suggested a role for TNF in
the development of insulin resistance in cells and animal disease
models. TNF is overexpressed in the adipose tissue of some diabetic
animals and patients (39, 40, 41, 42), and in some models TNF overexpression
appears to cause insulin resistance (43). Although TNF has been
shown to affect several aspects of insulin action (44, 45), an
additional possibility suggested by the findings reported here is that
overexpression of TNF in a diabetic state could lead to the
phosphorylation of PPAR via the JNK signaling pathway. Consequently,
as we have demonstrated, this phosphorylation would reduce the
effectiveness of activating ligands and could contribute to the
development of insulin resistance.
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Acknowledgments |
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Received April 20, 1998.
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 T. E. Akiyama, C. T. Baumann, S. Sakai, G. L. Hager, and F. J. Gonzalez Selective Intranuclear Redistribution of PPAR Isoforms by RXR{alpha} Mol. Endocrinol., April 1, 2002; 16(4): 707 - 721. [Abstract] [Full Text] [PDF]
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Z. E. Floyd and J. M. Stephens Interferon-gamma -mediated Activation and Ubiquitin-Proteasome-dependent Degradation of PPARgamma in Adipocytes J. Biol. Chem., February 1, 2002; 277(6): 4062 - 4068. [Abstract] [Full Text] [PDF]
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A. Warnmark, A. Wikstrom, A. P. H. Wright, J.-A. Gustafsson, and T. Hard The N-terminal Regions of Estrogen Receptor alpha and beta Are Unstructured in Vitro and Show Different TBP Binding Properties J. Biol. Chem., November 30, 2001; 276(49): 45939 - 45944. [Abstract] [Full Text] [PDF]
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W. Yang, Y. H. Hong, X.-Q. Shen, C. Frankowski, H. S. Camp, and T. Leff Regulation of Transcription by AMP-activated Protein Kinase. PHOSPHORYLATION OF p300 BLOCKS ITS INTERACTION WITH NUCLEAR RECEPTORS J. Biol. Chem., October 12, 2001; 276(42): 38341 - 38344. [Abstract] [Full Text] [PDF]
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M. Iwata, T. Haruta, I. Usui, Y. Takata, A. Takano, T. Uno, J. Kawahara, E. Ueno, T. Sasaoka, O. Ishibashi, et al. Pioglitazone Ameliorates Tumor Necrosis Factor-{alpha}-Induced Insulin Resistance by a Mechanism Independent of Adipogenic Activity of Peroxisome Proliferator-Activated Receptor-{gamma} Diabetes, May 1, 2001; 50(5): 1083 - 1092. [Abstract] [Full Text]
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 Q. N. Diep, R. M. Touyz, and E. L. Schiffrin Docosahexaenoic Acid, a Peroxisome Proliferator-Activated Receptor-{alpha} Ligand, Induces Apoptosis in Vascular Smooth Muscle Cells by Stimulation of p38 Mitogen-Activated Protein Kinase Hypertension, November 1, 2000; 36(5): 851 - 855. [Abstract] [Full Text] [PDF]
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 E. D. Rosen, C. J. Walkey, P. Puigserver, and B. M. Spiegelman Transcriptional regulation of adipogenesis Genes & Dev., June 1, 2000; 14(11): 1293 - 1307. [Full Text]
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K. Bordji, J.-P. Grillasca, J.-N. Gouze, J. Magdalou, H. Schohn, J.-M. Keller, A. Bianchi, M. Dauca, P. Netter, and B. Terlain Evidence for the Presence of Peroxisome Proliferator-activated Receptor (PPAR) alpha and gamma and Retinoid Z Receptor in Cartilage. PPARgamma ACTIVATION MODULATES THE EFFECTS OF INTERLEUKIN-1beta ON RAT CHONDROCYTES J. Biol. Chem., April 14, 2000; 275(16): 12243 - 12250. [Abstract] [Full Text] [PDF]
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R. Hi, S. Osada, N. Yumoto, and T. Osumi Characterization of the Amino-terminal Activation Domain of Peroxisome Proliferator-activated Receptor alpha . IMPORTANCE OF alpha -HELICAL STRUCTURE IN THE TRANSACTIVATING FUNCTION J. Biol. Chem., December 3, 1999; 274(49): 35152 - 35158. [Abstract] [Full Text] [PDF]
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 B. Desvergne and W. Wahli Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism Endocr. Rev., October 1, 1999; 20(5): 649 - 688. [Abstract] [Full Text]
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J. E.-B. Reusch and D. J. Klemm Editorial: Nutrition and Fat Cell Differentiation Endocrinology, July 1, 1999; 140(7): 2935 - 2937. [Full Text]
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H.-Y. Lee, Y.-A. Suh, M. J. Robinson, J. L. Clifford, W. K. Hong, J. R. Woodgett, M. H. Cobb, D. J. Mangelsdorf, and J. M. Kurie Stress Pathway Activation Induces Phosphorylation of Retinoid X Receptor J. Biol. Chem., October 6, 2000; 275(41): 32193 - 32199. [Abstract] [Full Text] [PDF]
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J. B. Hansen, H. Zhang, T. H. Rasmussen, R. K. Petersen, E. N. Flindt, and K. Kristiansen Peroxisome Proliferator-activated Receptor delta (PPARdelta )-mediated Regulation of Preadipocyte Proliferation and Gene Expression Is Dependent on cAMP Signaling J. Biol. Chem., January 26, 2001; 276(5): 3175 - 3182. [Abstract] [Full Text] [PDF]
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K. J. Waite, Z. E. Floyd, P. Arbour-Reily, and J. M. Stephens Interferon-gamma -induced Regulation of Peroxisome Proliferator-activated Receptor gamma and STATs in Adipocytes J. Biol. Chem., March 2, 2001; 276(10): 7062 - 7068. [Abstract] [Full Text] [PDF]
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R. A. Memon, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold In Vivo and in Vitro Regulation of Sterol 27-Hydroxylase in the Liver during the Acute Phase Response. POTENTIAL ROLE OF HEPATOCYTE NUCLEAR FACTOR-1 J. Biol. Chem., August 3, 2001; 276(32): 30118 - 30126. [Abstract] [Full Text] [PDF]
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P. M. Barger, A. C. Browning, A. N. Garner, and D. P. Kelly p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor alpha . A POTENTIAL ROLE IN THE CARDIAC METABOLIC STRESS RESPONSE J. Biol. Chem., November 21, 2001; 276(48): 44495 - 44501. [Abstract] [Full Text] [PDF]
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