COMMUNICATION
Regulation of Protein Phosphatase 2A Activity by Heat Shock
Transcription Factor 2*
Yiling
Hong and
Kevin D.
Sarge
From the Department of Biochemistry, University of Kentucky,
Chandler Medical Center, Lexington, Kentucky 40536-0084
 |
ABSTRACT |
Heat shock transcription factor (HSF) mediates
the stress-induced expression of heat shock protein genes
(hsp). However, HSF is required for normal cell function
even in the absence of stress and is important for cell cycle
progression, but the mechanism that mediates these effects of HSF is
unknown. Here, it is shown that a member of the HSF family, HSF2,
interacts with the PR65 (A) subunit of protein phosphatase 2A (PP2A).
HSF2 binding to PR65 blocks its interaction with the catalytic subunit,
due to competition between HSF2 and catalytic subunit for the same
binding site in PR65. In addition, overexpression of HSF2 stimulates
PP2A activity in cells, indicating the relevance of HSF2 as a regulator of PP2A in vivo. These results identify HSF2 as a dual
function protein, capable of regulating both hsp expression
and PP2A activity. This could function as a mechanism by which
hsp expression is integrated with the control of cell
division or other PP2A-regulated pathways.
 |
INTRODUCTION |
HSF1 is a transcription
factor that has a well characterized function in up-regulating the
expression of hsp genes following exposure of cells to
stress conditions, mediated by its binding to heat shock elements in
the promoters of these genes (1-6). However, a number of results
indicate that stress-induced hsp expression is not the only
function of HSF and in fact suggest that HSF is important for the
normal growth and development of cells. For example, the HSF gene is
essential for viability of yeast even under normal, nonstress
conditions (7-9), and deletion of the HSF gene in Drosophila
melanogaster results in defects in oogenesis and early larval
development, with evidence indicating that these defects are not due to
altered basal hsp expression but rather to some other as yet
unknown target or function of HSF (10). Further, a yeast cell cycle
mutant blocked in G2 was identified that maps to the HSF
gene, indicating that some function of HSF is important for progression
through the cell cycle (11).
Protein phosphatase 2A (PP2A) is involved in regulating a number of
important cellular processes including intermediary metabolism, signal
transduction, and cell cycle progression by dephosphorylating and
thereby modulating the activity of proteins that control these processes (12-16). PP2A is composed of a core heterodimer containing a
protein called PR65 (A subunit) and a catalytic subunit. This core
heterodimer associates with a large number of different B-type variable
subunits to form mixed populations of PP2A heterotrimers (holoenzyme)
in cells (17-24).
To gain insight into the functions of HSF in normal cellular growth and
development described above, we utilized the yeast two-hybrid approach
to identify cellular proteins that interact with HSFs. We found that a
member of the HSF family, HSF2, interacts specifically with the PR65
subunit of PP2A. Deletion mapping demonstrated that a region in PR65
previously shown to be involved in interacting with the catalytic
subunit is also required for binding to HSF2, suggesting that HSF2
directly competes with catalytic subunit for binding to PR65. This was
confirmed by our subsequent binding experiments. We also show that
overexpression of HSF2 leads to increased PP2A activity in cells,
indicating the relevance of HSF2 as a regulator of PP2A in
vivo. We hypothesize that the regulation of PP2A activity by HSF2
functions as a mechanism for cross-talk between the hsp
expression pathway and PP2A-regulated pathways in the cell, including
regulation of cell division.
 |
EXPERIMENTAL PROCEDURES |
Plasmids--
Bait constructs containing full-length mouse HSF1
and HSF2 were made in pGBD-C1 using standard subcloning methodologies.
3' truncation mutants of pGBD-HSF2 and pGAD-PR65 were made by
performing restriction digestion of selected unique sites, filling in
with T4 DNA polymerase, and then ligating to delete sequences from the
3' end. The sites in HSF2 utilized were SphI (pGBD-HSF2
(1-168)), TthIII (pGBD-HSF2 (1-281)), BglII
(pGBD-HSF2 (1-387)), and BamHI (pGBD-HSF2 (1-473)),
whereas the sites in PR65 used were BglII (pGAD-PR65
(1-325)) and Bsu36I (pGAD-PR65 (1-378)).
Yeast Two-hybrid Screening--
Bait constructs containing
full-length mouse HSF1 and HSF2 were made in pGBD-C1 and used to screen
a human brain cDNA library in yeast strain pJ69-4A, as described
previously (25, 26). Library plasmids that were scored positive by
their ability to confer growth on plates lacking adenine were isolated
and confirmed by back-transformation into pJ69-4A with the bait constructs.
-Galactosidase Assay--
For analysis of
-galactosidase
activity in yeast harboring two-hybrid constructs, yeast extracts were
incubated in 50 mM Na2HPO4/NaH2PO4 (pH
7.0), 10 mM KCl, 1 mM MgSO4, 50 mM
-mercaptoethanol. After addition of 1 mg/ml of
o-nitrophenyl-
-D-galactoside substrate, samples were incubated at 30 °C for 5 min, and then the
A420 nm was measured.
Expression of Recombinant Proteins and GST Pull-down
Assay--
Full-length HSF1, HSF2, PR65, and catalytic subunit were
subcloned into pQE30 (for His6 fusion proteins) or pGEX2T
(for GST fusion proteins), expressed in bacteria, and then purified
according to the manufacturer's instructions. For the in
vitro binding assay, GST-HSF1 or GST-HSF2 were bound to
glutathione-agarose beads, incubated with His6-PR65 for
1 h at 4 °C in binding buffer (20 mM Tris, pH 7.4, 50 mM NaCl, 0.1% Triton X-100, 14 mM
-mercaptoethanol). After washing four times with binding buffer,
bound PR65 was analyzed by SDS-PAGE and Western blot using anti-PR65
monoclonal antibodies (27). For competition binding experiments,
GST-PR65 was bound to glutathione-agarose, washed, and then incubated
in binding buffer with 1 µg of His6-catalytic subunit in
the absence or presence of increasing amounts (1 and 2 µg) of
His6-HSF2 or His6-HSF1 protein at 4 °C for
60 min. The beads were then washed four times with binding buffer, and
the binding of catalytic subunit was determined by Western blot using
anti-catalytic subunit polyclonal antibody (28, 29).
Immunoprecipitation Analysis--
Extracts of human K562
erythroleukemia cells made in Buffer C (20 mM HEPES, pH
7.9, 25% (v/v) glycerol, 0.42 M NaCl, 1.5 mM MgCl2, 0.2 mM EDTA, 0.5 mM
phenylmethylsulfonyl fluoride, 0.5 mM dithiothreitol) were
incubated with 4 µl of either HSF1 or HSF2 polyclonal antibodies for
1 h at 4 °C with gentle inversion mixing. Protein G-agarose was
added and incubated for 3 h at 4 °C with gentle mixing. After
collecting by centrifugation, the complexes were washed three times
with Buffer C, and the bound proteins then analyzed by SDS-PAGE and
Western blot using anti-PR65 antibodies (27). Levels of HSF1 and HSF2
in the extracts were determined by Western blot using HSF1 and HSF2
polyclonal antibodies (30). The experiments comparing levels of PR65 in
pellets versus supernatants of immunoprecipitations using
HSF2 and C
polyclonal antibodies were performed similarly except
that TBST buffer (10 mM Tris-HCl, pH 7.5, 150 mM NaCl, 0.2% Tween 20) was used instead of Buffer C and
that two sequential rounds of immunoprecipitation were done.
Supernatants of the immunoprecipitations were collected by
trichloroacetic acid precipitation, and then both pellet (pellets 1 and
2) and supernatant proteins were analyzed by Western blot using PR65 antibodies.
HSF2 Transient Transfection and PP2A Assay--
NIH 3T3 cells
were mock transfected or transfected with
-actin parental plasmid or
-actin-HSF2 using LipofectAMINE Plus (Life Technologies, Inc.)
following the manufacturer's protocol, and then extracts prepared from
these cells were assayed for PP2A activity by the method of Cohen
et al. (31) using 32P-labeled phosphorylase
a as substrate. The assay was performed in the presence and
absence of 3 nM okadaic acid, and PP2A activity was
determined by subtraction of the activity obtained in 3 nM okadaic acid from the total phosphatase activity (measured in absence
of okadaic acid).
 |
RESULTS |
To identify HSF-interacting proteins, a human brain yeast
two-hybrid library was screened using full-length mouse HSF1 or HSF2 as
bait (25, 26, 32, 33). One of the positives identified using the HSF2
bait was the protein PR65, which is a subunit of PP2A (34, 35). A
full-length clone of the PR65 protein was then tested for its ability
to interact with HSF2 in the yeast two-hybrid system (36). Yeast
transformed with the HSF2 bait plasmid and the full-length PR65 plasmid
(HSF2 + PR65) or with the HSF2 bait plasmid and the original PR65
partial clone (HSF2 +
PR65) are able to grow on media lacking
adenine, providing genetic evidence of an interaction between these
proteins (Fig. 1A). Yeast
transformed with the HSF2 plasmid and activation domain pACT2 plasmid,
HSF2 plasmid alone, or PR65 plasmid and Gal4-binding domain pGBD
plasmid are unable to grow on selective media (Fig. 1A).
PR65 interacts with a catalytic subunit protein (C
) to form the core
complex of PP2A (12-16), and therefore we also tested whether HSF2
interacts with the C
protein. Yeast transformed with the HSF2 bait
plasmid and a plasmid containing full-length C
(37) were not able to
grow on selective media, indicating that these two proteins do not
interact (Fig. 1A).

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Fig. 1.
Interaction between HSF2 and PR65 by yeast
two-hybrid assay. A, yeast strain pJ69-4A was
transformed with various plasmids and then plated on media lacking
adenine. The plasmid combinations tested were PR65 plasmid with pGBD
parental activation domain plasmid (PR65 + pGBD), HSF2 bait
plasmid alone (HSF2), HSF2 bait plasmid with pACT2
(HSF2 + pACT2), HSF2 plasmid with the partial PR65 clone
isolated from the library (HSF2 + PR65), HSF2 plasmid
with full-length PR65 plasmid (HSF2 + PR65), and HSF2
plasmid with catalytic subunit (HSF2 + C ) plasmid.
B, extracts prepared from yeast transformed with the plasmid
combinations described above were assayed for -galactosidase
activity.
|
|
To quantitate the interaction between HSF2 and PR65 in the yeast
two-hybrid system, we measured
-galactosidase activity in extracts
of yeast transformed with the same plasmid combinations tested above.
The results of this analysis confirm the ability of HSF2 to interact
with both full-length PR65 and the truncated PR65 clone originally
isolated from the library (
PR65) but not with the catalytic subunit
of PP2A (C
) (Fig. 1B). HSF2 shares several regions of
homology with its related family member HSF1 (25, 38, 39). However,
yeast transformed with an HSF1 bait plasmid and the full-length PR65
plasmid are not able to grow on selective media, indicating that these
two proteins do not interact and thus that the PR65 interaction is
specific to HSF2 (data not shown).
To provide additional evidence of the interaction between HSF2 and
PR65, we tested the ability of recombinant proteins to interact
in vitro using a GST pull-down assay. GST-HSF1 and GST-HSF2 were bound to glutathione-agarose, incubated with recombinant PR65, and
washed extensively, and then PR65 binding was measured by Western blot
analysis of proteins bound to the resin using PR65 antibodies. The
results of this experiment demonstrate that recombinant PR65 interacts
in vitro with GST-HSF2 but not GST-HSF1, providing
additional evidence of the HSF2-PR65 interaction as well as its
specificity (Fig. 2A). To
obtain evidence of interaction between endogenous HSF2 and PR65
expressed in cells, we also performed immunoprecipitation analysis. As
shown in Fig. 2B, PR65 is immunoprecipitated with HSF2
antibodies but not HSF1 antibodies, indicating that endogenous HSF2 and
PR65 proteins expressed in cells interact and that this interaction is
specific to HSF2.

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Fig. 2.
GST pull-down and immunoprecipitation
analysis of HSF2-PR65 interaction. A, GST-HSF1 and
GST-HSF2 were bound to glutathione-agarose, mixed with recombinant
PR65, and then washed to remove unbound protein. Bound PR65 was then
measured by SDS-PAGE and Western blot using anti-PR65 monoclonal
antibodies. B, HSF1 and HSF2 protein was immunoprecipitated
using HSF1 and HSF2 polyclonal antibodies, and then immunoprecipitated
proteins were subjected to Western blot using anti-PR65 monoclonal
antibodies. Levels of HSF1 and HSF2 protein in the extracts were
determined by Western blot using HSF1 and HSF2 polyclonal antibodies.
C, HSF2 and C in extracts of K562 cells and HeLa cells
were subjected to two rounds of immunoprecipitation using polyclonal
antibodies specific to each protein, and then immunoprecipitated
proteins present in pellet 1 (P1) and pellet 2 (P2) and proteins present in the supernatants of the
immunoprecipitations (S) were subjected to Western blot
using anti-PR65 monoclonal antibodies.
|
|
Next, we extended our immunoprecipitation analysis to determine what
proportion of the PR65 protein in the cell is associated with HSF2, by
comparing the amount of PR65 that is immunoprecipitated with HSF2
antibodies through two sequential immunoprecipitations (pellets 1 and
2) versus the amount that remains in the supernatant of the
immunoprecipitation. For comparison, we also determined the relative
proportion of PR65 that is immunoprecipitated with anti-C
antibodies. The results (Fig. 2C) demonstrate that a
significant proportion of cellular PR65 is immunoprecipitated with HSF2 antibodies.
To further characterize the HSF2-PR65 interaction, we examined the
regions of the HSF2 and PR65 polypeptides, which are important for this
interaction. We constructed 3' truncation mutants of each protein and
tested their ability to interact with the full-length partner in the
yeast two-hybrid system. The results demonstrate that 3' truncation
mutants of the HSF2 protein that terminate at amino acids 473 or 387 are able to interact with PR65, but further deletion of HSF2 protein to
amino acid 281 results in a loss of interaction with PR65 (Fig.
3A). For PR65, 3' truncation of the C-terminal region to amino acid 378 resulted in a loss of
interaction with HSF2 (Fig. 3B). These results suggest that the regions between amino acids 281 and 387 of HSF2 and between amino
acids 378 and 589 (wild type C terminus) of PR65 are required for
interaction.

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Fig. 3.
Deletion mapping of regions required for
interaction of HSF2 and PR65. C-terminal deletion mutants of HSF2
(A) and PR65 (B) were constructed and tested for
their ability to interact with the full-length partner in the yeast
two-hybrid system.
|
|
As indicated in Fig. 3B, a region of PR65 identified by our
deletion analysis to be required for interaction with HSF2 (amino acids
378-589) overlaps the region of this protein that was previously shown
to be involved in interacting with the catalytic subunit (28, 29, 40).
This suggested the interesting possibility that HSF2 could compete with
catalytic subunit for binding to PR65. To test this prediction, we
measured the binding of catalytic subunit to immobilized GST-PR65 in
the absence or presence of HSF2 protein. As shown in Fig.
4, the addition of HSF2 to the binding
reaction decreased binding of the catalytic subunit to PR65, whereas
the addition of HSF1 protein had no effect. Quantitation indicated that
the two amounts of HSF2 tested (1 and 2 µg) decreased catalytic
subunit binding to PR65 by 24 and 81.8%, respectively. These results
are consistent with the results of our interaction domain mapping
analysis above and indicate that HSF2 could function to sequester PR65
from catalytic subunit by competitive interaction.

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Fig. 4.
HSF2 competes with catalytic subunit for
binding to PR65. GST-PR65 was bound to glutathione-agarose and
then incubated with catalytic subunit in the absence or presence of
increasing amounts of HSF2 or HSF1 protein. After washing, the amount
of catalytic subunit bound to PR65 on the beads was determined by
Western blot using anti-catalytic subunit antibodies. Lane
C, control.
|
|
Previous results indicate that PR65 modulates the activity of the
catalytic subunit (36, 40-43). Therefore, the results shown above,
particularly the demonstration that HSF2 blocks the binding of
catalytic subunit to PR65, suggested that HSF2 could function as a
regulator of PP2A activity in vivo. To test this hypothesis, we determined whether overexpression of HSF2 protein in cells alters
PP2A activity. NIH 3T3 cells were transfected with an HSF2 expression
plasmid or the parental expression construct, and then PP2A activity in
extracts of these cells was measured by in vitro dephosphorylation assay using phosphorylase a as substrate.
The results show that overexpression of HSF2 leads to a significant increase in PP2A activity (2.7-fold) in cells (Fig.
5).

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Fig. 5.
HSF2 regulates PP2A activity in cells.
PP2A activity present in extracts of mock-transfected,
vector-transfected, and HSF2-transfected NIH 3T3 cells was assayed by
release of 32P from phosphorylase a in the
presence and absence of 3 nM okadaic acid. PP2A activity
was measured by subtraction of the activity obtained in 3 nM okadaic acid from the total phosphatase activity
(obtained in the absence of okadaic acid). Values are shown as
cpm/2 × 105 cells.
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|
 |
DISCUSSION |
HSF2 has previously been characterized as a transcriptional
regulator of hsp gene expression, particularly in cells
undergoing differentiation and development (44-47). However, our
results now suggest that in addition to its role as a transcription
factor, HSF2 also has a novel and unexpected function as a regulator of PP2A activity. One possible hypothesis is that these dual functions of
the HSF2 protein evolved to provide a mechanism for cross-talk between
regulation of hsp expression and PP2A-regulated pathways, particularly pathways involved in control of cell division. This cross-talk could function to coordinate hsp expression with
the regulation of cell division or cell differentiation, to ensure the
presence of sufficient levels of molecular chaperones to meet the needs
of dividing or differentiating cells. However, we also recognize the
alternative possibility that the PP2A-regulating function of HSF2 may
be completely independent of its function in regulating hsp
expression. Indeed, previous results have indicated an apparent lack of
correlation between HSF2 and hsp expression during mouse
embryogenesis, leading to speculation that HSF2 may perform other
functions important for developing/differentiating cells (48). Similar
conclusions were drawn from studies in Drosophila, which
showed that deletion of the HSF gene causes developmental defects
without apparent effects on hsp expression
(10).
Our proposed model for HSF2 regulation of PP2A is shown in Fig.
6. In this model, we hypothesize that
HSF2 binding to PR65 prevents it from interacting with catalytic
subunit due to competition between HSF2 and catalytic subunit for the
same binding site in PR65. HSF2 expression is regulated during
development and differentiation (44-48), which could lead to changes
in the pool of PR65 available for association with catalytic subunit.
Because PR65 association modulates the activity of the catalytic
subunit (36, 40-43), this could lead to alterations in cellular PP2A
activity. Thus, we think that HSF2 could represent a new type of
PP2A-regulatory protein, distinct from the B-type regulatory proteins
that also interact with PR65 but in the context of associated catalytic subunit (17-24) (Fig. 6). The biological significance of our
hypothesized function of HSF2 in regulating the availability of PR65
for binding to catalytic subunit is clearly demonstrated by results
showing that mutations in PR65 that disrupt its ability to interact
with catalytic subunit are associated with human lung and colon cancers (49).

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Fig. 6.
Model of HSF2 regulation of PP2A
activity. In the model, "free" catalytic subunit is not meant
to imply that this protein could not be interacting with other
protein(s), only that it would not be associated with PR65.
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|
In summary, the results of our study extend the function of HSF2 beyond
its classical role as a regulator of hsp expression to
include a new role as a modulator of cellular PP2A activity. Thus,
fully understanding HSF2 activity in cells will require us to elucidate
both of these functional roles and their relationship to each other,
which could provide insight into the mechanisms of cross-talk that link
important signaling pathways in cells.
 |
ACKNOWLEDGEMENTS |
We thank Marc Mumby for full-length
constructs of PR65 and C
, Gernot Walter for antibodies against PR65
and C
, and Tom Vanaman also for PR65 and C
antibodies. We
acknowledge Michael Goodson for amplifying the brain library and
establishing yeast two-hybrid technology in the laboratory.
 |
FOOTNOTES |
*
This work was supported by startup funds from the University
of Kentucky, a Basil O'Connor Award from the March of Dimes, National
Institutes of Health Grant HD32008 (to K. D. S.), and Fellowship Support (for Y. H.) from the Vice President for
Research and Graduate Studies, University of Kentucky.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.
To whom correspondence should be addressed. Tel.: 606-323-5777;
Fax: 606-323-1037; E-mail: kdsarge{at}pop.uky.edu.
 |
ABBREVIATIONS |
The abbreviations used are:
HSF, heat shock
transcription factor;
PP2A, protein phosphatase 2A;
GST, glutathione
S-transferase;
PAGE, polyacrylamide gel
electrophoresis.
 |
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