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Departamento de Fisioloxía, Facultade de Medicina, Universidade de Santiago de Compostela (J.A.C., R.S., J.D., V.M.A.), San Francisco s/n. 15705, Santiago de Compostela, Spain; and INSERM U-344, Endocrinologie Moléculaire, Faculté de Medicine Necker (J.F., S.M.), 75730 Paris Cedex 15, France
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Abstract |
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454GHR) of the GH receptor in which GH induces a sustained
activation of the receptor-associated tyrosine kinase JAK2, we found
that GH stimulation inhibited programmed cell death induced by
withdrawal of survival factors. This effect was enhanced in cells
expressing the truncated form. In contrast, GH did not affect cell
survival in CHO cells transfected with either the empty vector or a
mutated GHR unable to transduce the signal (4P/AGHR). We also showed
that the inhibitory action of GH on apoptosis is probably mediated via
stimulation of the serine-threonine kinase Akt, as 1) GH treatment
induces a prompt phosphorylation of Akt; and 2) GH effects on cell
survival are abolished by transfection of an Akt mutant that exhibits
dominant negative function. Experiments with pharmacological inhibitors
demonstrated that GH-induced Akt phosphorylation is dependent on
phosphoinositide 3-kinase activation. In contrast, we found no changes
in Bcl-2 levels secondary to GHR activation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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GH stimulates growth principally by increasing the synthesis and release of insulin-like growth factor I (IGF-I) by the liver and other organs. IGF-I, in turn, promotes cell survival in many tissues and cell proliferation in some. In addition, GH can also promote growth by acting in a direct way, inducing the proliferation of different cell types (1, 2). Surprisingly, a direct effect of GH on cell survival has not been investigated to date.
We show here that GH acts as a survival factor in HL-60 cells, a human
leukemic cell line that express both GH and GH receptor (GHR) (7, 9).
To better characterize the signaling pathway involved in this effect,
we used Chinese hamster ovary (CHO) cells stably expressing either the
wild-type or two different mutated forms of the GH receptor: the
4P/AGHR, which bears a quadruple substitution of the four prolines in
box 1 that renders the receptor inactive (10); and the 454GHR, a
truncated form of the receptor that lacks residues beyond position 454,
resulting in persistent activation of the GHR-associated tyrosine
kinase JAK2 (11). Our data support the idea that GH also acts as a
survival factor in CHO cells expressing the GHR. Moreover, the
antiapoptotic pathways induced by GH appear to be to some extent
constitutively activated in cells expressing the
carboxyl-terminal-deleted form of the receptor.
As phosphoinositol 3-kinase (PI-3K) and Akt have been recently shown to play a major role in the regulation of survival mechanisms in several cell types, including fibroblasts, epithelial cells, hemopoietic cells, and primary neurons (12, 13, 14, 15, 16, 17), we investigated the potential activation of this pathway by GH, and its role in the regulation of GH-induced cell survival. We show for the first time that GH activates Akt and that the GH effect is blocked by using specific inhibitors of PI-3K activity and by an Akt mutant (PKB-CAAX) that exhibits a dominant negative function (18). Together, our results demonstrate that GH inhibits apoptosis and suggest that the PI-3K/Akt pathway could play a major role in this effect.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CHO, CHO-4P/AGHR, CHO-wtGHR, and CHO-454GHR stable clones,
respectively, carrying an empty vector with selectable marker
(pcDNA3/Flag), a 4P/AGHR construct (10), a Flag-tagged wtGHR construct,
or a Flag-tagged 454GHR construct (19) were grown in Ham’s F-12
medium (Life Technologies, Inc.) supplemented with 10%
FCS (Life Technologies, Inc.) and 2 mM
L-glutamine (Sigma Chemical Co.) at 37 C in
5% humidified CO2. PI-3K inhibitors (wortmannin and
LY294002) were purchased from Sigma and used at 10
nM and 10 µM, respectively. Human recombinant
GH (Saizen, Serono, Madrid, Spain) was used at 1 µg/ml.
GH binding analysis
For binding studies, cells were seeded in six-well plates
(106 cells/well). After 4-h serum starvation, cells were
incubated overnight at 4 C with [125I]GH (105
cpm/ml) in the absence or presence of increasing concentrations of
unlabeled GH at 4 C in PBS-0.1% BSA. After incubation, the cells were
washed with cold PBS and lysed in 0.1 N NaOH. Total
radioactivity associated with the cells was measured in a 
-counter.
Scatchard analyses were performed with the Ligand program (20).
Survival assays
Cells were harvested in lysis buffer [10 mM Tris, 1
mM EDTA (pH 8), and 0.2% Triton X-100], incubated for 20
min on ice, and centrifuged. The supernatants were then precipitated
overnight at -20 C in 50% isopropanol and 0.5 M
NaCl, and precipitated DNA was pelleted by centrifugation. Pellets were
then resuspended, treated with ribonuclease A (100 µg/ml, 1 h,
37 C) and proteinase K (300 µg/ml, 2 h, 50 C), and resolved in
1.5% agarose gel. Ethidium bromide-stained DNA laddering was
visualized with a Gel Doc System (Bio-Rad Laboratories, Inc., Hercules, CA).
Immunoblot analysis
For Akt stimulation experiments, cells were maintained in 1%
FBS for 48 h, followed by serum starvation for 2 h. Cells
were then lysed by adding SDS sample buffer [62.5 mM
Tris-HCl (pH 6.8), 2% SDS, 10% glycerol, 50 mM
dithiothreitol, and 0.1% bromophenol blue]. Cell extracts were
resolved in 12% SDS-PAGE and electrotransferred onto nitrocellulose
paper (Protran, Schleicher & Schuell, Inc., Dassel,
Germany). Membranes were then probed with a commercial kit
(Phosphoplus Akt Ser473 Antibody Kit, New England Biolabs, Inc., Beverley, MA) that allows specific recognition of
both nonphosphorylated and serine-phosphorylated Akt.
For Bcl-2 levels determination, cells were processed as described above, and membranes were probed with a polyclonal anti-Bcl-2 antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA).
Transient transfections
Both CHO-wt and CHO-454 cells were transfected with the
Fugene 6 transfection reagent (Roche Molecular Biochemicals, Mannheim, Germany) according to the
manufacturer’s instructions. Briefly, cells were plated in chamber
slides the day before the transfection experiment and grown until 70%
confluent. Afterward, cells were serum starved, and transient
transfections were performed with 2 µg green fluorescent protein
(GFP) expression construct (pEGFP-C1, CLONTECH Laboratories, Inc., Palo Alto, CA) or 2 µg PKB-CAAX (provided by B.
M. T. Burgering, Utrecht University, Utrecht, The Netherlands) and
2 µg pEGFP-C1. Cells were given either recombinant GH (as indicated
above) or vehicle. After 24 h, nuclei were stained with the DNA
dye bisbenzimide (Hoeschst 33258, Sigma Chemical Co.).
Transfected cells were identified by GFP fluorescence and scored for
apoptosis by nuclear morphology.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In contrast,
GH treatment increased cell survival, although this effect was delayed.
As shown in Fig. 1A, when serum-starved HL-60 cells were grown for 9
days in the presence of GH, DNA laddering was reduced compared with
that in cells treated with vehicle (Fig. 1A).
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454GHR. Binding characteristics of these clones
were determined by Scatchard analysis. The Kd (0.7 and 0.9
nM, respectively) and number of binding sites per cell
(16,500 and 18,200, respectively) were similar in both types of cells.
We also used a CHO clone expressing a Box1 mutant of the receptor
(4P/AGHR). The binding characteristics of these cells, which are unable
to activate JAK2 under GH stimulation, have been reported (10), and
they are also comparable to those of cells expressing the wt GHR.
In CHO cells expressing the wtGHR, we observed that serum
withdrawal resulted in rapid apoptosis (Fig. 1B
). The dying cells
showed characteristic features of apoptosis, including nuclear
condensation and membrane blebbing (Fig. 1C). Similar results were
obtained in control CHO cells transfected with the empty vector (Fig. 1B). When serum-starved wtGHR cells were incubated with GH, cell death
was reduced, although some apoptotic cells and chromatin cleavage were
still present. In contrast, GH treatment did not induce any effect in
control cells (Fig. 1B) or in cells expressing the inactive receptor
(4P/A GHR). In both cases, serum starvation induced extensive cell
death after 32 h that was not counteracted by GH treatment (Fig. 1, B and C).
We also tested the viability of CHO cells expressing the GHR mutant,
which allows the sustained activation of JAK2 (454GHR).
Interestingly, after 32 h of serum deprivation, we observed
abundant healthy 454GHR-expressing cells. These cells showed well
defined nuclei and large cytoplasms, whereas DNA laddering was almost
absent, indicating increased survival. However, cell viability under
serum starvation was barely affected by GH treatment in these cells
(Fig. 1, B and C).
The GH antiapoptotic effect in CHO cells depends on Akt
activation
Akt, a serine-threonine kinase that is the cellular homolog of the
v-akt oncogene (21) is one of the key factors in the
regulation of cell survival. As this kinase conveys survival signals
from various cell surface receptors, including members of the cytokine
receptor superfamily, we then tested the possible activation of Akt by
GH in cells expressing either the wt or the truncated form of the GHR
(454GHR). We observed that GH induced a rapid phosphorylation of Akt
in both types of cells (Fig. 2A). This
activation of Akt appears to be dependent on PI-3K activity, as
suggested by the fact that GH was ineffective in promoting Akt
phosphorylation in the presence of two unrelated PI-3K inhibitors:
wortmannin and LY294002 (Fig. 2B).
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454GHR cells with an Akt mutant (PKB-CAAX) that exhibits dominant
negative function and, therefore, inhibits growth factor-induced
phosphorylation of Akt (18). Transfected cells were identified by
cotransfection with a plasmid encoding the marker gene GFP. Expression
of the dominant negative Akt induced apoptosis in both wt and
454GHR cells during serum starvation (Fig. 3), resulting in a 4-fold increase in the
number of apoptotic cells (Fig. 4).
Treatment with GH did not reverse this effect (Figs. 3 and 4),
suggesting that Akt is a downstream effector of the GH effect.
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454GHR. Under these experimental conditions,
we were unable to find any change in Bcl-2 (Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first used a human leukemic cell line (HL-60) to show that GH can act as a survival factor. It has been reported that GH treatment of these cells is able to increase cell growth (9, 27). As this effect could be mediated by an increase in cell survival, we first analyzed the ability of GH to reduce serum starvation-induced apoptosis in these cells. Our results clearly support this hypothesis. Moreover, as these cells are known to express and release GH (5, 7), we used anti-GH antibodies to test the role of the endogenously expressed hormone. We demonstrate that the addition of GH antibodies results in a significant increase in chromatin cleavage. Therefore, with this cellular model we can show that either endogenously produced hormone or exogenous addition of GH can affect cell viability through the endogenous GH receptors.
To characterize more easily the signaling pathways responsible for this effect, we used CHO cells transfected with either the wtGHR or different mutated forms. The early steps in GHR signaling involve ligand-induced receptor homodimerization, which results in the association and activation of JAK2, the GHR-associated tyrosine kinase. Once activated, JAK2 promotes the phosphorylation of a cascade of target molecules, including the kinase itself and the cytoplasmic tail of the receptor (2). In turn, tyrosine phosphorylation of both JAK2 and the receptor provide docking sites for SH2 domain-containing molecules, including the Stat (signal transducer and activator of transcription) proteins, phosphatases, insulin receptor substrate-1 and -2 (IRS1 and -2), and PI-3K, as well as molecules involved in the activation of the Ras/mitogen-activated protein kinase pathway (28).
We and others previously reported that truncation of the cytoplasmic
tail of the receptor (454GHR) results in prolongation and
enhancement of the early steps of GHR signaling, including JAK2, Stat3,
and IRS1 phosphorylation (11, 29, 30). The mechanisms responsible for
this sustained activation are poorly understood, but they could involve
the inactivation of JAK2 by SH2 domain containing tyrosine
phosphatase-1, a phosphotyrosine phosphatase that has been shown to
inactive GHR signaling. However, it has been shown that SHP-1
does not associate directly with the C-terminus of the GHR,
although this region is necessary for JAK2 dephosphorylation by the
phosphatase (30). Alternatively, the SOCS (suppressors of cytokine
signaling) molecules could also play a role in this down-regulation. GH
has been shown to induce SOCS1, -2, and -3 in 3T3F442A cells, and SOCS1
and -3 overexpression appears to inhibit GHR activation of a
Stat5-dependent reporter gene (31).
In this report we show that cell survival upon serum deprivation was
remarkably enhanced in CHO cells expressing 454GHR compared with
that in cells expressing the wtGHR. The partial effect of GH in
wtGHR cells could be explained by the fact that optimal cell survival
in vitro is often best supported by a combination of
survival factors, rather than a single factor (32, 33). On the other
hand, it is possible that the acute stimulation of GHR in wtGHR induced
a transient activation of GHR signaling secondary to the inactivation
of JAK2. Alternatively, GHR signaling may be terminated by
internalization and degradation of the GH-GHR complex (34, 35).
Although the molecular mechanisms for this down-regulation appear
complex (involving protein synthesis, proteasome-mediated protein
degradation, tyrosine phosphatase activation, and serine threonine
kinase activation), it is likely that one or several of them may be
absent in the cells expressing the truncated mutant, thus explaining
why the GH survival effect might be enhanced in these cells.
As we observed that activation of the GHR can inhibit the programmed cell death induced by serum starvation, we investigated whether this effect was due to a direct stimulation of survival pathways by GH. We first checked whether this effect was dependent on JAK2 activation, using a GHR with mutations in box 1 (4P/AGHR) that prevent interaction of this domain with JAK2, thus inactivating the transduction of the signal (10, 36). As expected, when activation of JAK2 was impeded, GH treatment was ineffective in reducing cell death induced by serum starvation.
Another molecule recruited and activated by GHR is PI-3K (37). Recruitment of PI-3K can occur through tyrosine-phosphorylated IRS1, and its activation results in the generation of phosphoinositide products that act as second messenger molecules and activate a number of intracellular targets (21). Among them, Akt was recently shown to convey survival signals from various cell surface receptors (19, 38), including members of the cytokine receptor superfamily (24, 25). Activated Akt phosphorylates and thus inactivates a number of targets, such as the proapoptotic protein Bad (38, 39, 40), glycogen synthase kinase-3 (41), caspase-9 (42), and a forkhead transcription factor (43, 44). Although PI-3K is the major kinase involved in Akt phosphorylation, other pathways of Akt activation, independent of PI-3K, have been described. Hence, it has recently been reported that in NG108 neuroblastoma cells, calcium promotes phosphorylation of Akt through a PI-3K-independent mechanism that involves Ca2+-calmodulin-kinase activation (45). Our results suggest that not only is GH-dependent Akt stimulation involved in GHR-induced cell survival, but it is also mandatory for this effect. Evidence for this is 2-fold: 1) GHR stimulation induces a prompt rise in Akt phosphorylation; and 2) the expression of the dominant-negative Akt produces deleterious effects that are not reversed by GH treatment. Moreover, the existence of a PI-3K-independent mechanism of Akt activation does not appear to be relevant in our experimental model, as the blockade of PI-3K pathways with wortmannin or LY294002 prevented Akt phosphorylation. In any case, we cannot discard that GH may induce the activation of other survival pathways, independent of Akt phosphorylation.
The fact that the truncated GHR mutant (454GHR) is able to fully
activate PI-3K/Akt, indicates that the amino acidic residues beyond
position 454 are not necessary for this signaling pathway. In fact, we
observed an increased activation of PI-3K/Akt in these cells that could
be related to the increased IRS1 phosphorylation by the truncated
receptor, as discussed above. Interestingly, this membrane-proximal
region of the cytoplasmic domain of the GHR is also sufficient for
activation of mitogenic pathways depending on Stat3 or
mitogen-activated protein kinase (46, 47, 48), thus supporting its key role
in GHR signaling.
Akt activation induced by cytokine treatment also promotes expression of Bcl-2 in certain cell types, although this is not a constant finding (12, 24, 25). These changes occur very quickly after stimulation, as in the case of IL-2, where increased expression of Bcl-2 appeared within 10 min (25). In contrast, we did not find any change in Bcl-2 levels induced by GH treatment, thus suggesting that in our experimental model, the effects of Akt on cell survival are not dependent on changes in Bcl-2.
Together, our results show that GHR stimulation delivers an antiapoptotic signal in both HL-60 cells and CHO cells transfected with active forms of GHR. This effect appears to be mediated by PI-3K activation, with subsequent Akt phosphorylation, but is independent of changes in Bcl-2 levels. We propose, on the basis of our results, that besides stimulating IGF-I synthesis and exhibiting a direct mitogenic effect on certain cell types, GH promotes growth by increasing cell survival. In view of these findings, GH could be considered a new member of the growing family of survival factors.
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Acknowledgments |
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Footnotes |
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1 This work was supported by grants from Fondo de Investigaciones
Sanitarias (94/1104 and 96/1522) and Xunta de Galicia (XUGA20803B96 and
XUGA20810B97). 
2 Recipient of a fellowship from Universidade de Santiago/Xunta de
Galicia.
Received June 24, 1999.
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