Received for publication, August 15, 2000, and in revised form, October 18, 2000
We subsequently determined whether RA-dependent
phosphorylation/activation of p38 occurs in an NB-4 variant cell line,
NB-4.007/6, which is refractory to RA-induced differentiation and
inhibition of cell growth, due to constitutive degradation of PML-RAR
(49). As shown in Fig. 2A,
when NB-4 and NB-4.007/6 cells were analyzed in parallel, the
phosphorylation of p38 was only inducible in NB-4 but not in NB-4.007/6
cells, despite the fact that similar amounts of the p38 protein were
expressed in both cell lines. Thus, functional activation of a
signaling cascade that requires PML-RAR expression is essential for
downstream phosphorylation/activation of the p38 kinase in cells of
acute promyelocytic leukemia origin.
We also determined whether RA-dependent activation of p38
occurs in the MCF-7 breast carcinoma cell line, which is sensitive to
the growth inhibitory effects of RA (50-52). RA treatment of these
cells resulted in a time-dependent phosphorylation of p38, with the signal reaching a maximum at ~24 h and diminishing by 120 h (Fig. 3, A and
B), indicating that the RA-inducible activation of p38 is
not restricted to cells of promyelocytic origin, but it also occurs in
other RA-sensitive neoplastic cells.
Previous studies have demonstrated that the small G-protein Rac1 is an
upstream regulator of the p38 MAP kinase in response to stress
(53-55). We therefore determined if Rac1 is activated in RA-responsive
manner and whether it regulates RA-inducible p38 activation. NB-4 or
NB-4.007/6 cells were treated for different times with RA, and cell
lysates were bound to a GST fusion protein for the binding domain of
the Pak1 kinase, which is the downstream effector for Rac1. The bound
proteins were subsequently analyzed by SDS-PAGE and immunoblotted with
an anti-Rac1 antibody to identify the activated/GTP-bound form of Rac1.
RA treatment induced strong activation of Rac1 in NB-4 but not in
NB-4.007/6 cells (Fig. 4A). Such activation was dose-dependent, with maximum amounts of
GTP-bound Rac1 detectable at RA concentrations of
10
5 to 10
6
M (Fig. 4B). Rac1 activation was also detected
in response to RA treatment in the MCF-7 cell line, consistent with the
RA-inducible p38 activation in these cells (Fig. 4C).
To determine directly whether Rac1 activation regulates downstream
engagement of p38, MCF-7 cells were transiently transfected with either
wild-type Rac1 or a dominant-negative form of Rac1 (Rac1T17N) (53). The
phosphorylation/activation of the p38 MAP kinase was subsequently
determined in the transfected cells. Overexpression of wild-type Rac1
slightly increased the RA-dependent activation of p38, as
compared with cells transfected with control empty vector (Fig.
5A). On the other hand,
overexpression of the dominant-negative form of Rac1 abrogated p38
activation (Fig. 5A). There were no changes in the amounts
of p38 protein in response to overexpression of wild-type Rac1 or the
dominant-negative Rac1 mutant (Fig. 5B). Thus, activation of
the Rac1 GTPase by RA ultimately regulates RA-dependent
activation of p38.
Altogether, these studies demonstrated that a cellular cascade
involving Rac1, the p38 MAP kinase, and the MAPKAPK-2 kinase is
activated by RA. In subsequent studies we sought to obtain information
on the functional relevance of this pathway in the induction of RA
responses. Previous studies have demonstrated that, in other systems,
the function of the p38 pathway is required for transcriptional
regulation (42-44, 57). It is also well established that one of the
mechanisms of action of RA involves RA-dependent up-regulation of the transcriptional activator Stat1 (58-62). Such Stat1 up-regulation may be particularly important for the induction of
the synergistic effects of RA and type I interferons (59-61), which
also activate the p38 MAP kinase pathway (42-44). In addition, there
is recent evidence that p38 may be required for serine phosphorylation of Stat-1 in response to various stimuli (63-65). We therefore sought
to determine whether inhibition of RA-dependent p38
activation abrogates RA-dependent gene transcription, as
well as serine phosphorylation and/or up-regulation of Stat1 protein expression.
We first performed studies to determine whether SB203580, which
selectively blocks p38 activation, abrogates gene transcription via
RARE elements. MCF-7 cells were transfected with a plasmid containing
an RARE-luciferase construct and treated with RA in the presence or
absence of the SB203580 inhibitor. The RA-dependent induction of luciferase activity was subsequently determined. As
expected, RA treatment of cells resulted in a significant increase in
luciferase activity (Fig. 7A).
Treatment of cells with SB203580 did not abrogate such
RA-dependent induction of luciferase activity (Fig.
7A), indicating that the function of the p38 pathway is not
required for RA-induced transcriptional regulation. We also determined
whether p38 inhibition blocks up-regulation of Stat1 protein expression
by RA. NB-4 cells were incubated with RA for 48 h, and the cells
were lysed, and total cell lysates were analyzed by SDS-PAGE and
immunoblotted with a monoclonal antibody against the
serine-phosphorylated form of Stat1 on Ser-727 (Fig. 7B) or against Stat1 (Fig. 7C). Consistent with previous reports
(59-62), significantly higher levels of Stat1 were detectable in the
RA-treated samples (Fig. 7C). Also, there was an increase in
the level of Stat1 phosphorylated on Ser-727 after treatment of cells
with RA (Fig. 7B). However, treatment of the cells with
SB203580 did not affect Stat1 protein expression (Fig. 7C)
or Stat1 serine phosphorylation (Fig. 7B), indicating that
the p38 pathway does not exhibit regulatory effects on RA-induced
up-regulation of Stat1.
We subsequently determined the effects of inhibition of p38 activation
on the induction of RA-dependent cell differentiation of
NB-4 cells. Cells were treated with RA in the presence or absence of
SB203580, and the induction of differentiation was determined by
staining the cells with the CD11b antibody, whose expression is a
marker for RA-induced myeloid differentiation. As shown in Fig.
8, RA treatment induced up-regulation of
CD11b expression. Surprisingly, concomitant treatment with SB203580
strongly enhanced RA-dependent CD11b expression (Fig. 8).
To confirm that the p38 pathway plays a negative regulatory role on the
induction of cell differentiation, another specific p38 inhibitor,
SB202190, was studied. Consistent with the effects obtained using
SB203580, treatment of cells with SB202190 strongly enhanced the
induction myeloid differentiation of NB-4 cells in response to RA (Fig. 8). On the other hand, inhibition of ERK kinase activation using the
PD98059 inhibitor abrogated RA-dependent up-regulation of CD11b (Fig. 8), consistent with previous reports (20). Thus, in
contrast to the function of the ERK pathway that exhibits positive regulatory effects on RA-mediated myeloid cell differentiation (20),
the p38 pathway antagonizes such effects.
In further studies, we sought to identify the functional role of the
p38 MAP kinase pathway in the generation of the growth inhibitory
effects of RA on NB-4 cells. Cells were treated with RA in the absence
or presence of SB203580, and cell proliferation was assessed using an
MTT assay. As expected, RA diminished cell proliferation of NB-4 cells
(Fig. 9). Concomitant treatment of cells
with SB203580 at doses of 5 or 10 µM further enhanced the growth inhibitory effects of RA on these cells, whereas treatment with
SB203580 alone had no significant effect on cell growth (Fig. 9). Thus,
in addition to regulating RA-dependent cell
differentiation, the p38 pathway appears to play a negative regulatory
role in the generation of growth inhibitory responses by RA on target cells.
The family of MAP kinases includes the ERK, JNK, and p38 kinases
(reviewed in Ref. 66). These kinases are activated in response to a
variety of stimuli and mediate signals important for the generation of
various biological responses (66). Two members of this family, ERK2 and
JNK, have been previously shown to be involved in the generation of
retinoid responses. ERK2 is activated in response to
all-trans-retinoic acid treatment in the HL-60 acute
myelogenous leukemia cell line (20), and such an activation is
apparently required for the induction of RA-dependent cell differentiation and growth arrest. This has been established by studies
demonstrating that treatment of cells with a specific inhibitor of ERK2
activation, PD98059, reverses the effects of RA on these cells (20).
Other studies have established that RA inhibits JNK
kinase-dependent signaling pathways (19) via activation of
the MAP kinase phosphatase-1 (MKP-1) and abrogation of MKK4 activity
(67). Although the precise functional role of inhibition of JNK kinase
activity by RA is unknown, it has been proposed that this inhibition
may mediate the suppression of c-Fos expression by RA to
facilitate growth inhibition (19).
In the present study we provide the first evidence that the p38 MAP
kinase is activated by all-trans-retinoic acid treatment of
target cells. Our data clearly establish that RA treatment induces
phosphorylation of p38 and induction of its kinase activity in two
RA-sensitive cell lines, NB-4 and MCF-7. Furthermore, they demonstrate
that the small G-protein Rac1 is activated by RA and that its function
is essential for RA-induced p38 activation. The activation of Rac1 and
p38 eventually leads to engagement of the MAPKAPK-2 kinase, which
functions as a downstream effector for this pathway.
Surprisingly, we found that treatment of cells with the p38 inhibitors
SB203580 or SB202190 strongly enhances RA-induced differentiation, whereas inhibition of ERK kinase activity using the PD98059 inhibitor partially reverses such differentiation, confirming that the ERK kinase
pathway mediates such responses. The pyridinyl imidazole compounds
SB203580 and SB202190 specifically inhibit p38 activation by binding to
the ATP site and inhibiting its kinase activity (71). Both of these
inhibitors exhibit the same specificity and block activation of the p38
(p38
) and p38
isoforms but not p38
and p38
(25, 27, 32,
71). Thus, it is possible that, in addition to p38
, p38
is also
activated by RA and exhibits negative regulatory effects on
differentiation, although this needs to be determined in future
studies. The specificity of our findings is also established by the
fact that another MAP kinase inhibitor, PD98059, which inhibits
activation of ERK kinases, but not p38, blocks RA-induced
differentiation. Our data also implicate p38 as a negative regulator on
the RA-induced growth inhibitory activities and such a finding is
consistent with its effects on RA-induced cell differentiation, as
differentiated cells exhibit lower proliferation potential.
Altogether, our data implicate the activation of the p38 pathway by RA
treatment in the negative regulation of induction of differentiation
and growth inhibition. Such a function for p38 may represent a novel
mechanism to control the rate of RA-dependent differentiation and apoptosis of normal cells, also conserved in
malignant cells. However, the precise signals downstream of p38 that
mediate such negative regulatory effects remain to be determined. It
has been previously shown that the ERK and p38 pathways cross-talk and
compete with each other for the induction of certain biological
responses and that inhibition of ERK leads to p38 activation (72).
Thus, the negative regulatory effects of p38 on RA-induced
differentiation and growth inhibitory responses may be mediated via an
antagonistic effect on ERK2, but this remains to be established in
future studies. Recent studies have also shown that retinoic acid
induces the up-regulation of mRNA for blr1, a chemokine
receptor that promotes activation of ERK2 and RA-dependent
cell differentiation (73). Thus, the negative regulatory effects of p38
activation on RA-induced responses may be mediated by down-regulation
of blr1 expression. If this hypothesis proves to be correct,
it would provide a mechanism by which the opposing effects of the ERK
and p38 MAP kinases on the induction or RA-dependent cell
differentiation occur.
Independent of the precise mechanisms involved, the finding that
pharmacological inhibition of the p38 MAP kinase pathway enhances
RA-dependent differentiation and growth arrest may prove of
clinical value in the future. RA is used successfully in the treatment
of acute promyelocytic leukemia and several other malignancies (1-4)
but resistance to its effects eventually develops in nearly all cases.
It is conceivable that combined use of RA with pharmacologic agents
that inhibit p38 may enhance its differentiating and growth inhibitory
effects in vivo. Further studies along these lines may
provide important insights on the mechanisms by which
all-trans-retinoic acid and other retinoids generate their
biological effects, and provide the basis for the rational development
of novel therapeutic approaches in RA-responsive malignancies.
We thank Joanna Woodson for technical
assistance and Dr. Eleanor N. Fish for carefully reading this manuscript.
Published, JBC Papers in Press, November 1, 2000, DOI 10.1074/jbc.M007431200
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