From the Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118
Received for publication, December 21, 2000, and in revised form, March 12, 2001
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ABSTRACT |
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Endothelins exert their biological effects
through G protein-coupled receptors. However, the precise mechanism of
downstream signaling and trafficking of the receptors is largely
unknown. Here we report that the histone acetyltransferase Tip60 and
the histone deacetylase HDAC7 interact with one of the ET receptors, ETA, as determined by yeast two-hybrid analysis, glutathione
S-transferase pull-down assays, and co-immunoprecipitation
from transfected COS-7 cells. In the absence of ET-1, Tip60 and HDAC7
were localized mainly in the cell nucleus while ETA was predominantly
confined to the plasma membrane. Stimulation with ET-1 resulted in the internalization of ETA to the perinuclear compartment and
simultaneously in the efflux of Tip60 and HDAC7 from the nucleus to the
same perinuclear compartment where each protein co-localized with the receptor. Upon co-transfection with ETA into COS-7 cells, Tip60 strongly increased ET-1-induced ERK1/2 phosphorylation, whereas HDAC7
had no significant effect. We thus suggest that protein acetylase and deacetylase interact with ETA in a
ligand-dependent fashion and may participate in ET signal transduction.
The endothelin family consists of three known members, ET-1, ET-2,
and ET-3,1 all of which have
potent vasoconstrictive activity (1, 2). In addition, endothelins
control many other cellular processes including gene expression,
cytoskeletal reorganization, differentiation, and cell growth (3-9).
They can also stimulate secretion of neuropeptides, pituitary hormones,
and atrial natriuretic peptide from neural and neuroendocrine cells
(10-12) and induce translocation of Glut4-containing vesicles in
3T3-L1 adipocytes (13, 14).
Endothelins interact with the specific G protein-coupled receptors A
(ETA) and B (ETB). The extracellular N terminus of these receptors is
involved in ligand binding, whereas the intracellular C-terminal region
is implicated in downstream signaling, receptor internalization, and
desensitization (15-19). ET-1 interacts mainly with ETA, whereas the
affinity of ET-2 and ET-3 to this receptor is much lower (20). In
contrast, ETB has similar specificity for all three endothelin subtypes
(21).
The diversity of endothelin action may be explained not only by the
multiplicity of ligands and receptor heterogeneity but also by the
ability of the receptor to activate different signaling pathways.
Binding of ET-1 to ETA leads to the increase in intracellular calcium
levels via activation of phospholipases A2, C, and D and Ca2+ channels (22-26). It has also been documented that
ET-1 activates the MAP kinase pathway (27-29). The sequence of
biochemical events in which ETA and other heptahelical receptors
activate this pathway is not clear and may depend on the cell type.
Several possible mechanisms have been proposed. For example, Src and/or
other upstream signal-transducing proteins may interact with these
receptors directly or through arrestin (30-32). Also, ET-1 and several
other ligands may turn on ERK1/2 by "transactivation" of the
receptor-tyrosine kinase; in particular, the epidermal growth factor
receptor (33-35). Yet another mechanism involves calcium and tyrosine
phosphorylation of PYK2 (36, 37). It has also been shown that
internalization of G protein-coupled receptors and/or transactivation
of receptor-tyrosine kinases is crucial for the activation of the MAP
kinase pathway (38, 39).
Binding of ET-1 to ETA causes rapid receptor internalization via
clathrin-coated pits and/or caveolae (40, 41). Internalized ETA then
traffics through the endosomal pathway to the pericentriolar recycling
compartment that can also be marked by fluorescent-labeled transferrin
(42). Eventually, a significant fraction of ETA recycles back to the
plasma membrane (42, 43).
To identify novel proteins that interact with ETA and may affect its
biological functions, we have utilized the yeast two-hybrid system
using the ETA C-terminal region as bait. Two ETA-interacting proteins
were identified: a histone acetyltransferase (HAT) Tip60 (44) and a
human homolog of mouse HDAC7 (45) that represents a new member of the
histone deacetylase (HDAC) family. We have further shown that HAT and
HDAC proteins undergo ET-1-dependent translocation from
nucleus to cytoplasm, where they co-localize and interact with ETA.
Moreover, co-expression of Tip60 with ETA significantly potentiated
phosphorylation of ERK1/2 in response to ET-1 stimulation. We propose
that Tip60 and HDAC7 act as novel components of ETA-mediated signal transduction.
Materials--
The following antibodies were used for
this work: monoclonal anti-Myc antibody (InVitrogen), monoclonal
anti-FLAG antibody (Sigma), monoclonal anti-p44/42 MAP kinase (Erk1/2)
antibody (New England Biolabs), monoclonal anti-phospho-p44/42 MAP
kinase antibody (New England Biolabs), polyclonal anti-ETA antibody
(46), polyclonal anti-Tip60 antibody (Upstate Biotechnology),
Cy3-conjugated anti-rabbit and FITC-conjugated anti-mouse IgG
(Jackson Immunoreserach Laboratory), horseradish peroxidase-conjugated
anti-rabbit and anti-mouse IgG (Sigma) and affinity-purified
nonspecific mouse IgG (Sigma). Other reagent grade chemicals were from Sigma.
Cell Culture--
Transformed African monkey kidney cell line
COS-7 and rat smooth muscle cell line A10 were maintained in high
glucose Dulbecco's modified Eagle's medium (DMEM, Life
Technologies, Inc.) with 10% fetal bovine serum (Hyclone) in a
37 °C, 5% CO2 incubator.
Plasmids--
The rat ETA cDNA (40) was subcloned into the
HindIII site of pRC-CMV (Promega). The bait DNA,
ETAC/pAS2-1, was constructed as described below. The ETA C-terminal
region, which consists of amino acids 365-420 of rat ETA, was
amplified from full-length ETA in pRC-CMV vector by PCR and cloned into
the PstI site of pAS2-1 vector
(CLONTECH).
The C-terminal region of ETA (amino acids 365-420) was amplified by
PCR, conjugated in frame with glutathione S-transferase (GST) in pGEX-4T1 vector (Amersham Pharmacia Biotech), and was named ETACGST.
To add Myc and polyhistidine epitopes to the C-terminal end of ETA, the
latter was subcloned into pcDNA3.1Myc-His(+) vector. The stop codon
at the end of ETA in pRCCMV vector was deleted, a XbaI site
was introduced by the QuikChange site-directed mutagenesis kit
(Stratagene), and this product was introduced into the
pcDNA3.1Myc-His(+) vector A by both HindIII and
XbaI digestion. This construct was named ETAmychis.
Yeast Two-hybrid Screening--
The cloned bait DNA,
ETAC/pAS2-1, and human brain library DNA, in pACT10 vector, were
co-transformed into yeast strain CG1945, and positive clones were
selected. Positive clones were further selected for those that
specifically interact with the ETA C-terminal region but not with other
proteins (p53, lamin, and GAL4 DNA-binding domain alone) and the
cDNAs were isolated from these clones and sequenced.
The Tip60 cDNA obtained by two-hybrid screening was subcloned into
pFLAG-CMV2 vector (Kodak/Sigma) using the SalI and
XbaI-digested vector. HDAC7 cDNA corresponding to the
C-terminal fragment of the protein (amino acids 545-824) was cut with
EcoRI and BglII and ligated into the pFLAG-CMV2
vector that was cut with EcoRI and XbaI. This
vector is referred to as ctHDAC7/pFLAG-CMV2.
The full-length cDNA for Tip60 was obtained from the human brain
library by PCR. The PCR product was then digested with KpnI and DrdI. The partial Tip60 cDNA in the pFLAG-CMV2
vector was cut with DrdI and XbaI. The pFLAGCMV2 vector was
cut with KpnI and XbaI, and all three fragments
were ligated together. This vector was named Tip60/pFLAGCMV2.
The full-length cDNA of HDAC7, DKFZp586J0917
(GenBankTM/EBI accession no. AL117455), was obtained from
the human genome center (RZPD) in Heidelberg, Germany. The cDNA was
cloned into the pFLAGCMV2 vector and this vector was named
HDAC7/pFLAGCMV2.
Transfection--
Plasmids (4 µg each) were transfected into
COS-7 cells using LipofectAMINE Plus reagent (Life Technologies, Inc.)
and cells were harvested or stained after 72 h of transfection.
Cells were washed twice with cold PBS and harvested in the extraction
buffer (25 mM Tris, pH 7.4, 1% Triton X-100, 1 µg/ml
leupeptin, 1 µg/ml aprotinin, 1 µg/ml pepstatin, and 1 mM PMSF). For the analysis of ERK1/2 phosphorylation, 5 µM Trichostatin A (Takara Inc.), 1 mM
Na3VO4, and 20 mM NaF were added to
the extraction buffer. After incubation on ice for 15 min, the extract
was centrifuged at 14,000 rpm for 5 min to remove cell debris. The
protein concentration in supernatant was determined by Pierce BCA
protein assay.
GST Pull-down Assay--
ETACGST (which comprises the entire
sequence of the ETA C terminus) and GST alone were purified as
described (47). Beads were blocked with 10 mg/ml BSA (Sigma) at RT for
30 min. The extracts from the Tip60- or HDAC7-transfected cells were
added and incubated with the beads at RT for 1 h. Beads were
washed twice (5 min each) with the binding buffer and then twice with
the binding buffer containing 0.5 M NaCl. Equal volumes of
2× sample buffer were added to washed beads for 10 min at 95 °C,
and the supernatant was analyzed by Western blot.
Co-immunoprecipitation Experiments--
Transfected cells were
harvested and anti-Myc antibody or nonspecific mouse IgG (1 µl each)
were added to the cell extracts (0.5-1 mg) and were incubated
overnight at 4 °C with rotation. Protein G-Sepharose beads (30-50
µl; Amersham Pharmacia Biotech), blocked with 2% BSA in PBS for 30 min at 4 °C, were added to the mixture and incubated for 2 h at
4 °C. The beads were washed once with the binding buffer (see the
previous paragraph) at 4 °C for 10 min and four times with the
binding buffer containing 0.5% sodium deoxycholate. The beads were
then rinsed once with 10 mM Tris, pH 7.4 and eluted with
equal volumes of 2× sample buffer at 65 °C for 10 min. The eluates
were analyzed by Western blot.
Immunofluorescence Experiments--
Cells on coverslips were
washed with cold PBS and fixed with 4% paraformaldehyde solution for
30 min at RT. Cells were solubilized with 0.1% Triton X-100 in PBS for
5 min at RT and then rinsed with PBS three times. Primary antibody in
PBS with 5% BSA and 3% donkey serum was added for 30 min at RT. The
cells were washed with PBS for 30-60 min and Cy3- or FITC-conjugated
secondary antibody (2-4 µg/ml in the same solution as primary
antibody) was added to the cells for another 30 min. The cells on
coverslips were washed overnight in PBS at 4 °C and mounted on
slides. The fluorescent images were analyzed with the help of the
LSM510 Zeiss confocal microscope.
Subcellular Fractionation of A10 Cells--
Rat vascular smooth
muscle cells A10 were incubated in the absence or presence of ET-1
(10 To identify proteins interacting with ETA, the human brain
cDNA library (~8 × 105 clones) was screened
with the C-terminal region of ETA (amino acids 365-420) as a bait
using the yeast two-hybrid system. The final selection process yielded
two strong positive clones. A BLAST search revealed that the first
clone was identical to Tat-interactive protein 60 or Tip60 (44), which
belongs to the subfamily of histone acetyltransferases called MYST
(49). The second clone encoded a novel protein with a region of strong
homology to the conserved catalytic domain of the class II histone
deacetylases, which includes HDAC4, HDAC5, and HDAC6 (50). According to
a recent report (45), this protein represents a human homolog of mouse HDAC7.
To confirm interaction of Tip60 and HDAC7 with ETA, GST-conjugated
peptide corresponding to the C terminus of ETA was used in GST
pull-down experiments. Fig. 1a
demonstrates that Tip60 and ctHDAC7 bind to ETACGST but not to GST
alone. These results confirm the direct interaction between the ETA C
terminus and Tip60 or HDAC7 in vitro.
INTRODUCTION
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
8 M) for 30 min and separated into nuclei
and cytoplasmic fractions as described (48).
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Fig. 1.
Interaction of Tip60 and HDAC7 with ETA
in vitro and in vivo. a,
purified GST proteins (2 µg each) were incubated with extracts
(10-20 µg) of Tip60 or ctHDAC7 expressing COS-7 cells. Proteins were
isolated with glutathione beads (25 µl of packed beads) and were
analyzed by Western blot with anti-FLAG antibody. A representative
result from at least three independent experiments is shown.
b, co-immunoprecipitation of Tip60 and ctHDAC7 with ETA.
ETAmychis was transfected into COS-7 cells alone or together with Tip60
or ctHDAC7 (both in the pFLAG-CMV2 vector). Cells were homogenized,
and ETAmychis was immunoprecipitated from cell lysates (500 µg) with
anti-Myc antibody (1 µg) and protein G-Sepharose (25 µl of packed
beads). Immunopurified proteins were analyzed by Western blot with
anti-FLAG antibody. A representative result from at least three
independent experiments is shown.
The interactions were further verified by co-immunoprecipitation experiments using transfected COS-7 cells. ETA with Myc epitope and poly(His) tag at the C terminus (ETAmychis) was expressed in COS-7 cells alone or co-expressed with either Tip60 or ctHDAC7 (both in the pFLAG-CMV2 vector) and immunoprecipitated with anti-Myc antibody. Western blot with anti-FLAG antibody demonstrates that both Tip60 and ctHDAC7 can interact with ETA in vivo (Fig. 1b). In control experiments, when cells were transfected with Tip60 or ctHDAC7 alone, no specific signal was detected in the immunoprecipitated material.
To study the intracellular localization of Tip60, HDAC7, and ETA,
transfected COS-7 cells were incubated in the presence or in the
absence of ET-1. These cells were immunostained with rabbit polyclonal
anti-ETA antibody, which specifically recognizes the N terminus of ETA
(46) and with monoclonal anti-FLAG antibody for the detection of Tip60
and HDAC7. Confocal images showed that in the absence of ET-1 ETA was
expressed mainly on the cell surface (Fig.
2). Tip60 (Fig. 2a) and HDAC7
(Fig. 2b) were detected mainly in the cell nucleus similar
to all other known histone acetyltransferases and deacetylases (50,
51).
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Treatment of cells with ET-1 changed the intracellular localization of all three proteins. As expected, ETA was internalized from the cell surface into the perinuclear region (Fig. 2, a and b). ET-1 stimulation also caused a dramatic redistribution of both Tip60 and HDAC7 from the nucleus into the same perinuclear region where these proteins co-localized with ETA. Note, that Fig. 2b shows two cells (bottom middle panel). One cell (transfected with both HDAC7 and ETA) demonstrates the redistribution of HDAC7 (green) from the nucleus to the ETA-containing perinuclear region upon ET-1 administration. Another cell (transfected with HDAC7 only) does not show this effect. Thus, expression of ETA is required for the ET-1-dependent nuclear efflux of HDAC7.
ET-1-induced efflux of Tip60 from the nucleus was confirmed in
biochemical experiments with non-transfected smooth muscle cells. A10
cells treated and not treated with ET-1 were separated into the nuclear
and the cytosolic fractions, and the presence of endogenous Tip60 in
these samples was analyzed by Western blot. It is evident in Fig.
3 that Tip60 is localized in the nucleus of basal cells and is partially relocated to the cytosol upon ET-1
stimulation.
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To determine whether or not Tip60 and/or HDAC7 are involved in the
downstream signaling of ETA, we analyzed the activation of p44/42 MAP
kinase (Erk1/2) in response to ET-1 stimulation. As described
previously (52, 53) and is also shown in Fig. 4, stimulation with ET-1 causes transient
activation of this pathway in COS-7 cells transfected with ETAmychis.
However, in cells transfected with ETAmychis together with Tip60, the
level of ET-1-induced ERK1/2 phosphorylation is dramatically increased,
which suggests that Tip60 may be directly involved in the acute
downstream signaling of ETA. Deletion of the C-terminal region of ETA
abolishes the effect of Tip60, indicating that direct interaction is
required for the elevation of ERK1/2 phosphorylation (data not
shown).
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The effect of exogenously expressed HDAC7 on the ERK1/2 pathway was
inconsistent. In some cases, ERK1/2 phosphorylation was attenuated,
whereas other experiments showed no effect (data not shown). However,
we were never able to detect an increase in ERK1/2 phosphorylation in
ETAmychis- and HDAC7-transfected cells.
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DISCUSSION |
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Acetylation/deacetylation of histones is crucial for the regulation of
transcription of many genes. Known substrates for HATs, however, are
not limited to histones and include several transcription factors,
importin, and -tubulin (54-59). Acetylation affects DNA-binding activity, protein stability, and protein-protein interaction (51). Therefore, acetylation and deacetylation may represent general post-translational modifications that take place in both nuclear and
cytosolic compartments of the cell (reviewed in Ref. 51). In fact, we
have shown that Tip60, a HAT family protein, can potentiate the effect
of ET-1 on ERK1/2 phosphorylation, which suggests that the acetylation
event may also regulate receptor-mediated signaling pathways.
Our studies on the localization of Tip60 and HDAC7 revealed that under basal conditions the major pools of Tip60 and HDAC7, like other HATs and HDACs, reside in the cell nucleus. ET-1 stimulation led to the redistribution of Tip60 and HDAC7 from the nucleus into the perinuclear region where each protein co-localized with the internalized ETA. Efflux of Tip60 and HDAC7 from the nucleus may have dual effects. First, it may result in changes in the transcription of several ET-1 responsive genes, such as c-myc, c-jun, c-fos, etc. Second, interaction of Tip60 and HDAC7 with ETA or ETA-associated proteins may affect cytoplasmic signaling pathways, such as phosphorylation of ERK.
It was recently shown that other class II histone deacetylases, HDAC4 and 5, shuttle between the nucleus and the cytosol (60, 61). The physiological importance of the nucleo-cytoplasmic distribution of HDAC4 and 5 was emphasized in a recent report demonstrating that muscle differentiation can be controlled by nuclear export of HDAC4 and 5 in response to calcium/calmodulin-dependent protein kinase signaling (62). On the other hand, constitutive activation of the MAP kinase pathway in Ras- or MEK1-transfected cells results in the increased nuclear localization of HDAC4 (63). ERK1/2 was shown to interact with and phosphorylate HDAC4, although it is not clear to what extent phosphorylation of HDAC4 may regulate its intracellular localization (63).
Our findings provide the first specific example of ligand-induced translocation of HAT and HDAC. However, the molecular mechanism(s) triggering the nuclear export of Tip60 and HDAC7 in response to ET-1 is not known. It is possible that interaction with internalized ETA may anchor Tip60 and HDAC7 in the cytosolic compartment and induce their efflux from the nucleus. There is evidence that protein 14-3-3 may play an important role in cytoplasmic retention of HDAC4 and 5 (61, 64). With the experimental system established in our study, future work should be able to ascertain the role of 14-3-3 or other candidate proteins in ET-1-induced nucleo-cytoplasmic transport of Tip60 and HDAC7.
In addition to the MAP kinase pathway, Tip60 and HDAC7 may be involved
in other regulatory events. For example, we have noticed that
transfection of cells with Tip60 increases (or with HDAC7 decreases)
the level of ETA (data not shown). This suggests that Tip60 may protect
ETA from degradation by re-routing the receptor from lysosomes to the
recycling pathway. We are now trying to follow up on these experiments
to uncover the potential role of acetylation/deacetylation in the
regulation of receptor trafficking and stability.
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ACKNOWLEDGEMENTS |
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We thank Dr. Ken Kosik for the human brain cDNA library. We also thank Dr. Seung-Jae Lee for reading the manuscript and his critical discussions.
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FOOTNOTES |
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* This work was supported by Grants DK52057 and DK56736 from the National Institutes of Health and by a research grant from the American Diabetes Association (to K. V. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Present Address: Parkinson's Inst., Sunnyvale, CA 94089.
§ Present Address: Millennium Pharmaceuticals, Cambridge, MA 02139.
¶ To whom correspondence should be addressed: 715 Albany St., Boston, MA 02118. Tel.: 617-638-5049; Fax: 617-638-5339; E-mail: kandror@biochem.bumc.bu.edu.
Published, JBC Papers in Press, March 21, 2001, DOI 10.1074/jbc.C000909200
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ABBREVIATIONS |
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The abbreviations used are: ET, endothelin; HAT, histone acetyltransferase; HDAC, histone deacetylase; Tip60, TAT-interactive protein of 60 kDa; MAP, mitogen-activated protein; FITC, fluorescein isothiocyanate; DMEM, Dulbecco's modified Eagle's medium; PCR, polymerase chain reaction; GST, glutathione S-transferase; PBS, phosphate-buffered saline; PMSF, phenylmethylsulfonyl fluoride; BSA, bovine serum albumin; RT, room temperature.
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