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Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084
Address all correspondence and requests for reprints to: Dr. Judy L. Meinkoth, Department of Pharmacology, University of Pennsylvania School of Medicine, 36th Street and Hamilton Walk, Philadelphia, Pennsylvania 19104-6084. E-mail: meinkoth{at}pharm.med.upenn.edu
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Introduction |
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The pp70/85-kDa S6 kinases (collectively referred to as
pp70s6k) regulate cell cycle progression via
phosphorylation of proteins important for transcription and
translation, including the transcription factor CREM
and the 40S
ribosomal protein S6 (reviewed in Ref.8). Activation of
pp70s6k is essential for cell cycle progression in many
cells (9, 10). cAMP, however, exerts differential effects on
pp70s6k activity. Although elevations in cAMP inhibited
pp70s6k activity in IL-2-responsive CTLL-20 cells (11),
epidermal growth factor-induced pp70s6k activity was
unaffected in Swiss 3T3 cells (12), in which cAMP stimulated
pp70s6k (13). The variability of the response to cAMP led
us to investigate whether cAMP-mediated activation of
pp70s6k was correlated with other effects of cAMP, such as
cell cycle progression. We now report that pp70s6k plays an
essential role in TSH-stimulated mitogenic signaling mediated by cAMP.
In addition to cultured rat thyroid cells, cAMP activates
pp70s6k in secondary rat Schwann cells and Swiss 3T3
fibroblasts, both cell types in which cAMP stimulates proliferation
(14, 15, 16). In contrast, in cells in which cAMP does not act as a
mitogen, it fails to stimulate pp70s6k activity. Our
results suggest that activation of pp70s6k plays a critical
role in cAMP-mediated cell cycle progression. The mechanism through
which cAMP-mediated mitogenic signals are directed to
pp70s6k remains to be determined, but is likely to include
phosphatidylinositol 3'-kinase (PI3K).
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Materials and Methods |
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-32P]ATP (6000 Ci/mmol) was obtained
from New England Nuclear (Boston, MA). FCS was purchased from Life
Technologies (Grand Island, NY). BSA was obtained from Bayer Scientific
(Kanakee, IL). All other reagents, including crude bovine TSH (1 U/ml),
wortmannin, forskolin, cholera toxin, and insulin, were purchased from
Sigma Chemical Co. (St. Louis, MO).
Cell culture
WRT cells and WRT cells stably transfected with a cAMP response
element (CRE)-regulated lacZ gene (WRT CRE) were cultured as
reported previously (2). These cells were rendered quiescent by
starvation in basal medium (Coon’s modified Ham’s F-12 medium
containing 0.3% BSA) for 48 h. For most experiments, basal medium
was further supplemented with insulin (0.5 µg/ml) to enhance the
mitogenic effects of TSH. However, similar results were obtained in all
experiments regardless of whether insulin was included in the
starvation medium (see Results). For wortmannin experiments,
BSA was deleted from basal medium. NIH-3T3 and REF52 fibroblasts were
propagated in DMEM supplemented with 10% FCS. Fibroblasts were
rendered quiescent by starvation in serum-free medium containing 0.5
µg/ml insulin for 30 h. Swiss 3T3 cells were maintained as
described previously (16). Cells (1 x 105) were
plated in 35-mm dishes, allowed to grow until confluent, and
subsequently starved in serum-free medium for 48 h. Secondary rat
Schwann cells were provided by Dr. J. Lynn Rutkowski (Department of
Neurology, University of Pennsylvania School of Medicine) and cultured
in DMEM supplemented with 10% FCS, forskolin (2 µM), and
bovine pituitary extract (15 µg/ml) (17). Schwann cells were rendered
quiescent by incubation in DMEM supplemented with 10% FCS for 96
h.
DNA synthesis measurements
Cells were labeled with bromodeoxyuridine (BrdU) for 24 h
(NIH-3T3, REF52, and Swiss 3T3) or 48 h (WRT and Schwann cells)
after treatment. DNA synthesis was assessed through incorporation of
BrdU and its subsequent detection by immunostaining (18).
CRE-regulated gene expression
Quiescent WRT CRE cells were stimulated with TSH (1 mU/ml) for
6 h and then fixed in 3.7% formaldehyde-PBS for 5 min at room
temperature. After fixation, the cells were stained in 5 mM
K3Fe(CN)6, 5 mM
K4Fe(CN)6, 2 mM MgCl2,
and 1 mg/ml
5-chloro-4-bromo-3-indolyl-ß-D-galactopyranoside (X-gal)
in PBS for 16 h at 37 C to detect ß-galactosidase (2).
Immunoblotting
Cells were lysed at 4 C for 20 min in ice-cold lysis buffer (10
mM KPO4, 1 mM EDTA, 5
mM EGTA, 10 mM MgCl2, 50
mM ß-glycerophosphate, 2 mM dithiothreitol,
1% Nonidet P-40, 1 mM Na3VO4, 1
mM Pefabloc (Boehringer Mannheim, Indianapolis, IN), and 10
µg/ml each of aprotonin and leupeptin). Soluble proteins were
denatured by boiling in Laemmli sample buffer, resolved on 7.5%
(pp70s6k) or 12.5% (phospho-S6) SDS-polyacrylamide gels,
and transferred to polyvinylidene fluoride membranes. After blocking
with PBS, 5% (wt/vol) milk, and 10% Tween, membranes were incubated
for 2 h with rabbit polyclonal anti-pp70s6k antibody
(0.5 µg/ml; sc-230, Santa Cruz Biotechnology, Santa Cruz, CA) or an
affinity-purified rabbit polyclonal antibody raised to a phosphorylated
peptide of S6 (amino acids 232–249; provided by Dr. M. Birnbaum,
Howard Hughes Medical Institute, Department of Medicine, University of
Pennsylvania). After incubation with alkaline phosphatase-conjugated
antirabbit antibody (1:1000; New England Biolabs, Beverley, MA) for
1 h, expression of pp70s6k or phosphorylated S6 was
detected using the CDP Star detection system (New England Biolabs).
pp70s6k immune complex kinase assay
Immunoprecipitates were prepared with rabbit polyclonal
anti-pp70s6k antibodies directed against the C-terminus
(Santa Cruz sc-230) or N-terminus (no. 06-265, Upstate Biotechnology,
Lake Placid, NY) for 16 h at 4 C. The immune complexes were
collected on protein A-Sepharose beads (Sigma P-7786) for 2 h at 4
C and washed three times with lysis buffer and twice with S6 kinase
buffer (20 mM HEPES, pH 7.4; 10 mM
MgCl2; and 1 mM dithiothreitol). Kinase
reactions were initiated by the addition of 50 µl S6 kinase buffer
containing 7.5 µg S6 peptide (RRRLSSLRA, Santa Cruz sc-3009), 20
µM ATP, 50 ng IP-20 (Sigma P-0300), and 10 µCi
[-32P]ATP. Reactions proceeded for 20 min at room
temperature and were terminated by spotting aliquots (20 µl) in
duplicate onto Whatman P81 paper (Whatman, Clifton, NJ). Filters were
washed three times for 5 min each time in 1% orthophosphoric acid,
immersed in ethanol, and dried before scintillation counting.
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Results |
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). Stimulation with TSH for 30 min
significantly retarded pp70s6k mobility. The TSH-stimulated
pp70s6k mobility shift was abolished by pretreatment with
rapamycin, an agent that specifically prevents the activation of
pp70s6k, but not the activation of the closely related
protein kinase pp90rsk (21, 22). The effects of TSH on
pp70s6k were mimicked by cAMP-elevating agents, including
forskolin (Fig. 1), 8-bromo-cAMP (8-BrcAMP), and cholera toxin (data
not shown), in a rapamycin-sensitive manner. These results supported a
role for pp70s6k in cAMP-mediated signaling.
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). Both TSH and
forskolin consistently stimulated a comparable 2-fold increase in
pp70s6k activity, which was inhibited by pretreatment with
rapamycin. Western blotting confirmed that equivalent amounts of
pp70s6k were immunoprecipitated from starved and stimulated
cells (data not shown). Although of modest magnitude, the effects of
TSH and forskolin on pp70s6k activity were observed with
two independent pp70s6k antibodies.
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). Low levels of phosphorylated S6
protein were observed in untreated cells. After treatment with TSH, S6
phosphorylation increased significantly, with maximal effects observed
at 30–40 min and persisting for up to 8 h (data not shown). This
time course correlated temporally with the phosphorylation of
pp70s6k, suggesting pp70s6k-mediated
phosphorylation of S6. Consistently, TSH-stimulated S6 phosphorylation
was inhibited by rapamycin (Fig. 2A), but not by dimethylsulfoxide
vehicle control (Fig. 2B). Forskolin also induced rapamycin-sensitive
S6 phosphorylation, indicating that the effects of TSH on
pp70s6k were mediated by cAMP (Fig. 2A). TSH-stimulated S6
phosphorylation was dose dependent, with significant S6 phosphorylation
only at TSH concentrations of 0.1 mU/ml or greater (Fig. 2C). A similar
dose response was obtained for the TSH-stimulated pp70s6k
mobility shift (data not shown). Consistent with the importance of S6
phosphorylation in the initiation of protein synthesis, a prelude to
cell division (8, 19, 20), the dose response for S6 phosphorylation
correlated with the dose response for TSH-stimulated DNA synthesis
(Fig. 3A). These data suggest a role for
pp70s6k in cAMP-mediated cell cycle progression.
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), but
not with vehicle, abolished TSH-stimulated DNA synthesis. These studies
were performed in cells starved in the presence of 0.5 µg/ml insulin,
because insulin enhances the mitogenic activity of TSH (Fig. 3C).
However, insulin is not required for either the mitogenic effect of TSH
(Fig. 3C) or TSH effects on pp70s6k activity and S6
phosphorylation (Fig. 2D). To determine whether pp70s6k was
also required for cAMP-mediated mitogenesis, cholera toxin- and
8-BrcAMP-stimulated DNA synthesis was examined. Pretreatment with
rapamycin blocked DNA synthesis in response to both cAMP-elevating
agents (Fig. 3B). Several experiments were performed to assess the kinetics of pp70s6k activation. Treatment with rapamycin at various times after TSH stimulation demonstrated a prolonged requirement for pp70s6k (data not shown), as has been shown in many other cells (9). DNA synthesis stimulated by TSH (86% BrdU-positive cells) or cholera toxin (78% BrdU-positive cells) was only slightly reduced by rapamycin pretreatment (65% and 60% BrdU-positive cells, respectively) when measured at 72 h, indicating a delay, rather than an abolition, of cell cycle progression, as has been observed in T lymphocytes (23). To ensure that rapamycin was stable over these extended times, the inhibitor was added at various times after TSH stimulation. Readdition of rapamycin failed to further decrease DNA synthesis (61% and 56% BrdU-positive cells, respectively), indicating that the inhibitor was not labile.
To confirm the specificity of rapamycin for pp70s6k in
these cells, its effects on CRE-regulated gene expression were examined
(Fig. 4). Although rapamycin (1–20
nM) induced slight changes in cell morphology, it did not
repress CRE-regulated gene expression, confirming that its inhibitory
effects on DNA synthesis were not due to effects on PKA activity. In
contrast, treatment with PKA inhibitors abolished CRE-regulated gene
expression (2, 24, 25). Together, these results demonstrate that
pp70s6k is required for TSH-stimulated DNA synthesis.
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). Similar to WRT cells,
cAMP-mediated DNA synthesis in these cells was repressed by
pretreatment with rapamycin. Consistently, forskolin retarded
pp70s6k mobility in Swiss 3T3 cells, an effect that was
blocked by rapamycin (Fig. 5A). Similar
effects were observed with cholera toxin in Schwann cells, although the
pp70s6k mobility shift in these cells was less robust than
that in the other cells due to the higher background of
pp70s6k activity in the presence of serum (data not shown).
Treatment of both Swiss 3T3 and Schwann cells with cAMP-elevating
agents significantly increased S6 phosphorylation in a
rapamycin-sensitive manner (Fig. 5B). Taken together, these results
suggest that pp70s6k is an important intermediate in
cAMP-mediated mitogenesis in at least three different cell types.
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). In contrast to
the effects of cAMP-elevating agents, serum treatment induced DNA
synthesis in these cells (80% BrdU-positive cells), retarded
pp70s6k mobility, and stimulated S6 phosphorylation in a
rapamycin-sensitive manner (Fig. 6). Similar results were observed in
REF52 fibroblasts (data not shown). These results suggest that
cAMP-mediated activation of pp70s6k is correlated with its
effects on mitogenesis.
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).
LY294002 or wortmannin (27) pretreatment also abolished TSH and
cAMP-mediated DNA synthesis (Table 3). As
a control for inhibitor specificity, the effects of LY294002 and
wortmannin on TSH-stimulated CRE-regulated gene expression were
examined. ß-Galactosidase expression was not detected (Fig. 4A; 0%
blue cells) in untreated WRT CRE cells. Treatment with TSH stimulated
ß-galactosidase expression in both the absence (Fig. 4B; 67% blue
cells) and presence of 30 µM LY294002 (64% blue cells)
or 200 nM wortmannin (68% blue cells). These results
suggest that PI3K is required for cAMP effects on pp70s6k
and proliferation.
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Discussion |
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One of the most interesting aspects of PKA-mediated signaling is its differential effects on cell proliferation. cAMP exerts inhibitory or stimulatory effects on proliferation depending upon the cell type (reviewed in Ref.32). The molecular mechanisms for these effects are poorly understood. In some cells in which cAMP inhibits growth, cAMP inhibits growth factor-stimulated MAPK activity (reviewed in Ref.7). However, there is no direct correlation between the effects of cAMP on MAPK activity and proliferation. In CCL39 cells, cAMP inhibits growth without inhibitory effects on MAPK (33), whereas in thyroid cells, cAMP stimulates proliferation in the absence of MAPK activation (4, 5). Mitogenic stimulation activates other protein kinases, including pp70s6k, an enzyme whose activity is essential for cell cycle progression in many cells (9, 10). In Swiss 3T3 cells, cAMP stimulates pp70s6k activity and DNA synthesis (13). Based on these results, we determined whether the stimulatory effects of cAMP on pp70s6k were correlated with its effects on mitogenesis.
The effects of cAMP-elevating agents on pp70s6k were examined in three cell types in which cAMP stimulates proliferation, a continuous line of Wistar rat thyroid cells, secondary rat Schwann cells, and Swiss 3T3 fibroblasts. The effects of cAMP in these cells were similar to those elicited by serum in fibroblasts: the stimulation of pp70s6k, S6 phosphorylation, and DNA synthesis. In all three cell types, cAMP-stimulated effects on pp70s6k, S6 phosphorylation, and DNA synthesis were abolished after treatment with rapamycin. The target of rapamycin in mammalian cells is mTOR, a protein encoding a putative lipid kinase domain homologous to PI3K (reviewed in Ref.22). Rapamycin is highly specific in its action, blocking activation of pp70s6k without effects on the closely related family member pp90rsk (21). In WRT cells, rapamycin failed to inhibit CRE-regulated gene expression even at concentrations 20-fold higher than those that abolished effects on pp70s6k and DNA synthesis, demonstrating that it does not impair PKA activity in these cells. These results also suggest that the pathways leading to CRE-regulated gene expression diverge before the requirement for pp70s6k in cAMP-mediated mitogenesis. These results are identical to those observed after inhibition of Ras in thyroid cells, where microinjection of a dominant negative Ras protein (2) or of an interfering Ras antibody reduced PKA-mediated DNA synthesis (Meinkoth, J. L., unpublished observations), but not CRE-regulated gene expression (2). Whether cAMP-mediated effects on pp70s6k are Ras dependent remains to be elucidated. However, Ras has been mapped both upstream and downstream from PI3K (reviewed in Ref.34) and both Ras-dependent and -independent pathways to pp70s6k have been reported (35, 36, 37, 38).
In contrast to the results in thyroid cells, Schwann cells, and Swiss 3T3 fibroblasts, cAMP failed to activate pp70s6k or stimulate S6 phosphorylation in NIH-3T3 or REF52 fibroblasts, cells in which cAMP does not stimulate DNA synthesis. These results suggest that in cells mitogenically responsive to cAMP, cAMP-mediated signaling is channeled through pp70s6k, much like the effects of serum growth factors in most cells. However, despite the similar effects of cAMP and serum growth factors on pp70s6k and DNA synthesis, these agents exhibit dramatically different effects on MAPK. cAMP fails to activate MAPK even in cells in which it stimulates proliferation (4, 5, 13).
The mechanism through which cAMP activates pp70s6k in a cell type-dependent fashion remains unclear. At least two potential mechanisms, one involving PI3K and another involving RalGDS, a guanine nucleotide exchange factor for RalA/B, can be envisioned for these effects. Inhibitors of PI3K either partially reduce or abolish growth factor-stimulated pp70s6k activity, indicating that PI3K is one mediator of pp70s6k activation (11, 39, 40, 41). In WRT cells, cAMP-mediated effects on pp70s6k activation and DNA synthesis stimulated by TSH were abolished by two independently acting PI3K inhibitors, suggesting that cAMP stimulates PI3K activity in these cells, although we have been unable to demonstrate this up to now. To our knowledge, stimulatory effects of cAMP on PI3K activity have not been reported. cAMP has been demonstrated to inhibit IL-2-stimulated PI3K activity in murine CTLL-20 cells (11), however, suggesting a potential for differential regulation in a cell type-specific manner. TSH-stimulated DNA synthesis is reduced by interference with RalGDS (5). Ral has been linked to multiple second messengers, including phospholipase D (42). A Ral-binding protein has been isolated that encodes a Cdc42 GTPase-activating protein (GAP) domain (43, 44, 45). This suggests another potential mechanism for TSH effects on pp70s6k, as both Cdc42 and Rac bind to the hypophosphorylated form of pp70s6k (46). Perhaps these small G proteins act to relocalize pp70s6k to the membrane, where it is subsequently activated by PI3K, Akt (47, 48), or other signals.
The existence of distinct mitogenic signaling pathways whose utilization varies in a cell type- and/or stimulus-dependent process is an emerging concept in signal transduction. cAMP exhibits differential effects on cell proliferation that are likely to be mediated through its differential regulation of a number of important growth-signaling molecules, including MAPK, pp70s6k, and perhaps PI3K. Such differential regulation provides one mechanism through which signal transmission can be directed to distinct signaling pathways, resulting in differential effects on cell biology.
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Acknowledgments |
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Footnotes |
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2 Member of the pharmacology graduate group at the University of
Pennsylvania.
Received September 10, 1997.
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(pp85) and 
