Vol. 131. No. 4 I’rinlrd in US A

Growth Factors Cells*

Hormone Synergizes with Serum Growth in Inducing c-fos Transcription in 3T3-F442A

GENEVIEVE Department

of

ASHCOMP,

GERI

Physiology,

University

GURLAND, of

Michigan

AND

JESSICA

Medical

SCHWARTZ

School, Ann Arbor, Michigan

48109

ABSTRACT GH is a major regulator of growth and metabolism, but cellular effects of GH alone have been difficult to demonstrate. Accordingly, suggestions have arisen that GH works in conjunction with other agents in producing its characteristic long term biological effects. In 3T3F442A cells, in addition to eliciting long term changes, GH rapidly increases the transcription of c-jos. The present study uses this rapid response to examine whether GH interacts with other factors early in its action, and whether such interactions lead to changes in gene expression. The induction of c-fos mRNA in response to the combination of GH (2.2 nM) and 10% calf serum or fetal calf serum was more than 3 times the additive effects of GH and either of the sera alone, indicating synergism between GH and serum. Insulin-like growth factor-1 (IGF-I), which also induces c-fos, had an effect with GH that was greater than the additive responses to the two agents. Nuclear run-off experiments indicated that the synergism between GH and IGF-I occurred at the level of transcription of c-jos. However, synergism between GH and serum in inducing c-fos transcription was greater than

synergism between GH and IGF-I, suggesting that factors in addition to IGF-I contribute to the interaction of GH with serum. Insulin and fibroblast growth factor also synergized with GH in inducing c-jos expression. Platelet-derived growth factor and epidermal growth factor appeared to induce c-jos additively with GH, suggesting that different types of interactions occur between GH and the various growth factors. In inducing c-&n, which works coordinately with c-jos in transcriptional regulation, the effect of GH was additive with that of IGF-I and synergistic with that of serum. These findings indicate that early in its action, GH interacts with other growth factors in inducing protooncogene expression in 3T3-F442A cells. Such interactions between GH and serum or specific growth factors result in synergistic induction of the expression of c-jos. These findings suggest a generalized mechanism in which a major contribution of GH to cellular growth regulation is to synergize with other growth-promoting signals early in transduction of such signals in target cells, resulting in enhanced gene transcription. (Endocrirzology 131: 1915-1921,1992)

I

with other serum factors, which are necessary as a backdrop for the differentiation-promoting activity of GH (8, 9). In serum-free medium, other growth factors are required for GH-promoted differentiation of 3T3-F442A cells (10). Thus, although it is now well recognized that GH does have direct effects in targets such as cartilage, preadipocytes, and adipocytes (ll-13), GH and other factors may interact in eliciting the long term biological effects considered to be characteristic of GH. Examination of oncogenes and protooncogenes has markedly advanced our understanding of early events in growth regulation (14, 15). In 3T3-F442A cells, we have demonstrated that GH rapidly increases transcription of the protooncogene c-fos (12). Expression of early response protooncogenes such as c-fos is among the earliest events associated with growth factor-stimulated growth and differentiation in various cell types (14-16). The resulting Fos protein is known to act as a transcription factor in 3T3-F442A cells in coordination with Jun (17). The Fos-Jun complex regulates the transcription of other genes that are likely to participate in long term events, such as those associated with differentiation (18). Studying the effects of GH in inducing c-fos mRNA thus provides a tool for gaining insight into early molecular events in GH action (12, 19, 20). The present study investigates whether interaction of GH with other factors occurs early in GH action and whether such interactions result in changes in gene expression by examining c-fos expression. Examina-

T IS PUZZLING that GH, a major regulator of normal growth and metabolism, elicits relatively small effects on cellular targets. Suggestions have arisen that GH does not act alone, but that it is effective through mediators or in combination with other agents. In the earliest studies on GH action, it was observed that GH alone was not as effective in promoting growth in hypophysectomized rats as it was in conjunction with very low doses of insulin (1). When cartilage was examined as an in vitro target, GH alone did not appear to be effective (2). Rather, the cartilage growthpromoting effect of GH seemed to be exerted through a circulating mediator, now known as insulin-like growth factor-1 (IGF-I) (3). Difficulty in demonstrating lipolytic effects of GH in adipose tissue in vitro led to the proposal that GH was permissive, i.e. effective in combination with other stimuli for lipolysis, such as glucocorticoids or starvation (4). In its capacity to promote differentiation of 3T3-F442A preadipocyte fibroblasts into adipocytes (5, 6) and of lOT,,z myoblasts into myotubes (7), GH appears to work in coordination Received March 25, 1992. Address all correspondence and requests for reprints to: Jessica Schwartz, Ph.D., Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622. *This work was supported by Grant DCB-8918289 from the NSF and grants from the Biomedical Research Council and the Office of the Vice-President for Research at the University of Michigan. t Supported in part by a Medical Student Research Fellowship from the University of Michigan. 1915

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GH AND GROWTH FACTORS SYNERGIZE IN INDUCING c-fos

1916

tion of the effect of GH in combination with growth factors in serum, including IGF-I, indicates that even at early time points, GH not only interacts but is synergistic with other growth factors in inducing c-fos expressionand transcription in 3T3-F442A cells. These findings suggest a generalized mechanism in which a major contribution of GH to cellular growth regulation is to synergize with other growth-promoting signals early in the transduction of such signals to the nucleus of target cells.

Materials and Methods Materials 3T3-F442A cells were provided by Dr. Howard Green (Harvard University, Boston, MA) and Drs. M. Sonenberg and R. Corm (SloanKettering, New York, NY). Media were purchased from Irvine Scientific (Santa Ana, CA), and sera from Whittaker (Walkersville, MD) or Gibco (Grand Island, NY). Methionyl human GH (lot K9016AX) was provided by Genentech (South San Francisco, CA). IGF-I (DSQ II) was a gift from Drs. L. Fryklund and A. Skottner (KabiVitrum, Stockholm, Sweden). Platelet-derived growth factor (PDGF; from human platelets or recombinant type BB), recombinant epidermal growth factor (EGF), and fibroblast growth factor (FGF; a mixture of acidic and basic) were obtained from Collaborative Research (Waltham, MA). BSA (preparation CRG-7) was purchased from Intergen (Purchase, NY). [32P]Deoxy-CTP and [“‘PI UTP were purchased from New England Nuclear (Boston, MA) or Amersham (Arlington Heights, IL).

Cell culture

and hormone

Endo. Vol131.

Results GH synergizes with serum in inducing

c-fos expression

GH is a major serum factor required for the differentiation of 3T3-F442A preadipocytes to adipocytes (5, 6). However, other serum factors are clearly involved in adipose conversion (6, 8, 9). To determine whether GH might interact with other serum growth factors in eliciting its rapid induction of c-fos expression in 3T3-F442A cells, the effect of GH was tested in combination with serum. Figure 1 shows that the induction of C-$X expression by 10% CS (lane B) or 10% fetal calf serum (FCS; lane C) was substantially greater when 2.2 nM GH was alsopresent. The responseto the combination of GH with CS or FCS (lanesE and F, respectively) was more than 3 times the additive effects of GH (lane D) and either of the sera alone, indicating synergism between GH and serum. Other experiments indicated that synergism also oc-

CON

CS

FCS

CON

+ GH CS FCS

treatment

3T3-F442A cells were grown to confluence in Dulbecco’s Modified Eagle’s Medium (DMEM) containing 4.5 g/liter glucose and 10% calf serum (CS), as described previously (12). Confluent 3T3-F442A preadipocytes were maintained in a quiescent state by incubation in DMEM containing 1% BSA for 18-24 h. Hormones or vehicle were added to the conditioned medium for various times and incubated at 37 C. When the effect of serum was tested, the conditioned medium was removed and replaced with DMEM containing serum, as indicated, and incubation proceeded as with hormone treatments. Control experiments in which conditioned medium was replaced with DMEM containing 1% BSA instead of serum gave results identical to those of control experiments in which vehicle was added to conditioned medium (12).

28 S-

4-

c-fos -

d-

tubulin

18 SNorthern

1992 No 4

blot analysis

Cells were harvested, and total RNA was prepared and analyzed by Northern blot analysis, as described previously (12). The cDNAs for mouse c-fos,mouse c-jun,rat ol-tubulin, and 28s ribosomal RNA have been previously described (12). The intensities of the bands obtained on autoradiograms were compared by laser scanning densitometry in the linear range. To control for possible variations in loading and transfer, these scans were routinely normalized to densitometric measurements obtained from probing the same blots with cDNA for a-tubulin or 28s rRNA. The normalized data were used for all comparisons.

Transcriptional

A

analysis

Cells were incubated with hormones or growth factors for 15 or 30 min at 37 C, nuclei were prepared, and transcriptional analysis was performed as described previously (12). Under the conditions of these experiments, when ol-amanitin was present, transcription was blocked. Quantification was determined by cutting and counting nitrocellulose filters and by densitometry of several exposures of autoradiograms in the linear range. Slight and inconsistent variability related to loading using control plasmids such as a-tubulin was substantially less than the consistent differences due to hormone treatment.

B

C

D

E

F

1. Synergism between GH and serum in induction of c-{OS expression. Quiescent 3T3-F442A preadipocytes were incubated for 30 min at 37 C with 10% CS (lanes B and E), 10% FCS (lanes C and F), or GH (2.2 nM; 50 rig/ml; lane D), alone or in combination. Total RNA (15 pg/lane) was subjected to Northern blot analysis using mouse c-fos and rat ol-tubulin cDNA probes. The positions of 28s and 18s ribosomal RNA are indicated in this and subsequent figures. Similar results were obtained in all four other experiments performed. CON, Control. FIG.

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GH AND

GROWTH

FACTORS

SY ‘NERGIZE IN INDUCING c-fos

cm-redwhen GH was added with 1% CS (not shown). Since previous experiments (12) indicate that induction of c-jos by GH is maximal at 50 rig/ml GH, GH in the serum is unlikely to contribute to the increase observed here, even if GH is present in serum at the highest levels reported, e.g. for FCS (64 &ml)

(21).

IGF-I participates

in the synergism

with GH

IGF-I was a likely candidate among serum factors to synergize with GH in inducing c-fos expression, since GH treatment of 3T3-F442A preadipocytes has been shown to increase greatly the sensitivity of the cells to the mitogenic effect of IGF-I (22). Figure 2 indicates that when GH (2.2 nM) was present in combination with IGF-I, the induction of c-fosmRNA by the two factors was substantially greater than their added effects. This synergism between GH and IGF-I was evident at 0.022, 2.2, 11, and 22 nM IGF-I. Figure 2B graphically represents the interaction between GH and IGFI in inducing the expression of c-fos. The synergism between GH and IGF-I was evident at the level of c-fos transcription (Fig. 3). Run-off transcriptional analysis indicated that GH (2.2 nM), IGF-I (2.2 nM), or 1% CS increased the transcription of c-fos after 30-min incuba-

tion. When cells were incubated with GH and IGF-I in combination, transcription of c-fos was almost twice as great as the added effects of GH and IGF-I alone, indicating synergism. Similar enhancement was observed after 15-min incubation of cells with the combination of GH and IGF-I (not shown). An even more marked synergism in c-jos transcription occurred when GH and 1% CS were tested in combination (Fig. 3, lane F) compared to GH and IGF-I in combination (lane D). Although CS alone (lane E) appeared no more effective than GH alone (lane B), the combined effect of GH and CS on c-fos transcription was 3 times greater than the added effects of GH and CS. This indicates that synergism of GH with IGF-I alone does not account for all interactions with serum factors, and suggeststhat GH interacts with other factors present in CS in inducing c-jos. In 3T3-F442A cells, Fos is known to complex with ]un in regulating the transcription of the gene for aP2, a lipidbinding protein (17, 18). Furthermore, GH induces c-jun as well as c-fos expression in these cells (12). It was therefore of interest to determine whether GH interacted with other growth factors in inducing c-jun as well as c-fos, Figure 3 demonstrates that the transcription of c-jun was increased by GH, IGF-I, or CS alone. The combination of GH with IGF-I appeared to increase transcription additively, in con-

B

A IGF-1 (nM) GH (2.2 nM)

0 b+

.022 E

c-fos +

0.22 fi

2.2 0

11 0

22 o+

-

28 S

-

18 S

1917

1.o11

ABCDEFGHIJKL

rl3NA-b

IGF-1

nM

FIG. 2. Synergism between GH and varying concentrations of IGF-I in inducing c-fos expression. Quiescent cells were incubated for 30 min with GH (2.2 nM) alone and in combination with varying concentrations of IGF-I. A, Northern blot analysis of total RNA (20 rg/lane). B, Graphical representation of densitometric analysis, expressed as relative intensity for c-fos normalized to rRNA. Shaded bars represent cells incubated without GH, and hatched bars indicate cells incubated with GH. Similar results were obtained in two other experiments.

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1918

GH AND A Con ---

c-fos c-fun a- tub pGEM

am

c

0 GH

IGF-I

Ime

9llu8

-

aR

GROWTH E

D GH + IGF-I

1% CS

FACTORS

SYNERGIZE

IN INDUCING

F

CON

INSULIN

c-fos EGF

Endo. Voll31.

1992 No 4

FGF

CGHCGH

GH + l%CS

JI J,

I,

0

FIG. 3. Synergism between GH and IGF-I or CS in stimulating protooncogene transcription. Nuclei obtained after 30-min incubation of cells with GH (2.2 nM; lanes B, D, and F), IGF-I (2.2 nM; lanes C and D), or 1% CS (lanes E and F), alone and in combination, were subjected to transcriptional analysis, as described in the text. Similar results were obtained in another experiment. a-tub, cu-Tubulin; Con, control.

trast to the synergism observed with c-jos. However, the effect of GH and CS on c-jun transcription was greater than additive compared to the effects of each agent alone. Thus, GH doesnot appear to regulate c-fos and c-jun in parallel, as observed previously (12).

28 S-

*

+

c-f*s

18 S-

A

0

C

D

EFGH

Interaction of GH with other growth factors in inducing c-fos expression To assesspossible interactions of GH with other growth factors, GH was tested in combination with insulin, EGF, or FGF (acidic and basic), each of which is known to increase c-fos expressionin other cell types in 30 min (14, 15). Figure 4 demonstrates that when GH was present in combination with the other growth factors, the induction of c-fos expression was greater than when GH was absent. When normalized to 28s ribosomal RNA (rRNA), the combination of GH and insulin or FGF, but not EGF, was greater than additive. PDGF is a potent growth factor and stimulator of c-fos expression (23). GH interacted additively with PDGF in inducing c-fos. It appeared to synergize with PDGF under some, but not all, conditions. For example, Fig. 5 shows that in the presence of 500 rig/ml (22 nM) GH, the increase due to 12.5 rig/ml PDGF (lane L) was greater than the added effects of GH and PDGF. At other concentrations of GH or PDGF, however, the induction of c-fos appeared to be additive. In three other experiments, GH and PDGF were at least additive in inducing c-fos mRNA, and occasionally, but inconsistently, were greater than additive. Comparing interactions of GH with the various concentrations of IGF-I or PDGF suggeststhat there are differences in the mode of interaction of GH with different serum growth factors, Discussion Synergism with growth factors is an early event in GH action: relation to later events These studies indicate that very early in its action, GH synergizes with serum factors in inducing expression of the early response protooncogene c-fos. In as little as 15 min, synergism between GH and serum was evident at the level of transcription of the protooncogene. Induction of c-fos expression is an early event in growth factor-stimulated differentiation (16), and Fosprotein participates, with Jun, in

FIG. 4. Interactions between GH and insulin, EGF, or FGF in inducing c-fos expression. Quiescent preadipocytes were incubated for 30 min with insulin (2.2 nM; lanes C and D), EGF (1.6 nM; lanes E and F), or FGF (0.75 nM; lanes G and H), alone and in combination with 2.2 nM GH, as indicated. Total RNA (15 pg/lane) was subjected to Northern blot analysis, as described in the text. For each agent, similar results were obtained in at least two other experiments.

regulating differentiation-dependent genes in 3T3-F442A cells (17, 24). Thus, the early induction of c-jos mRNA is thought to contribute to longer term events in adipocyte differentiation (18). GH is adipogenic in 3T3-F442A cells and represents at least 50% of the adipogenic activity of serum. However, it is clear that other serum factors are required for adipogenesisin conjunction with GH (6). This suggeststhat the synergism early in the interaction between GH and serum, which is detectable at the level of c-fos mRNA, contributes to longer term interactions between GH and serum which can culminate in adipocyte differentiation. Among many agents known to influence preadipocyte differentiation, two serum constituents, IGF-I and insulin, have been shown to be required in conjunction with GH to promote adipose conversion of 3T3-F442A cells. Exposure of 3T3-F442A preadipocytes to GH appears to prime young adipocytes to the mitogenic effect of IGF-I added in the presence of GH, resulting in clonal expansion of the adipocytes (22). The latter experiments were performed using medium containing cat serum (which itself has low adipogenie activity in the absenceof GH). Other experiments using a serum-free defined medium indicated that both GH and insulin (or IGF-I) were strictly required during the adipose conversion of 3T3-F442A cells (25). However, comparison to serum-containing medium substantiated that other serum factors were necessaryfor the clonal expansion of the young adipocytes incubated with GH and insulin. Thesestudies are

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GH AND GROWTH PDGF

(q/ml)

GH (nglml)

0~ 2.5 12.5 0

0____ 2.5 12.5 5

0_____ 2.5 12.5 50

FACTORS

0 2.5 12.5 500

4 -28s

c-fos-

Y, -18s

‘\

ABCDEFGH

rRNA

IJ



KL

-b

FIG. 5. Interactions between varying concentrations of GH and PDGF in inducing c-fos expression. Quiescent cells were incubated for 30 min with PDGF at 0, 2.5, or 12.5 rig/ml (0, 0.08, or 0.4 nM), alone (lanes A, B, and C, respectively) or in combination with varying concentrations of GH (5 rig/ml = 0.22 nM; 50 rig/ml = 2.2 nM; 500 rig/ml = 22 nM), as indicated. Total RNA (15 rg/lane) was subjected to Northern blot analysis, as described in the text.

consistent with the present observations that the synergism between GH and serum is at least twice as great as the synergism between GH and IGF-I in inducing c-fostranscription. The IGF-I was lesseffective than 1% CS in interacting with GH, even though the IGF-I was used at a level estimated to be present in 10% serum. This suggeststhat serum factors in addition to GH and insulin/IGF-I are involved in both early and later events. Interactions

between GH and IGF-I

Several lines of evidence indicate that IGF-I does not mediate the induction by GH of c-fos expression in 3T3F442A cells, although each agent does induce c-fos. This is based on the rapidity (15 min) of the effect of GH, which is faster than the most rapid (90 min) stimulation by GH of IGF-I gene expression reported (26, 27). In fact, in 3T3F442A cells, we have consistently found that GH does not regulate IGF-I mRNA or protein (Schwartz, J., et al., manu-

SYNERGIZE

IN INDUCING

c-fos

1919

script in preparation). In addition, GH is more effective in inducing c-fos mRNA than an equimolar concentration of IGF-I (12). It is notable that synergismwith other hormones or growth factors is a frequently recurring theme in IGF-I action. In addition to interacting with GH in the adipogenesisof 3T3F442A cells (22, 25), IGF-I was reported to synergize with FSH in the induction of several CAMP-dependent nonmitogenie ovarian granulosa functions (28). IGF-I and TSH were synergistic in stimulating DNA synthesis in FRLT5 thyroid cells (29), an effect that appears to involve additional autocrine factors as well (30). Furthermore, TSH and IGF-I each induce c-fos expression in FRLT5 cells (31, 32). In rabbit chondrocytes, progesterone or testosterone was reported to have a priming effect in increasing the ability of IGF-I to stimulate DNA and sulfated proteoglycan synthesis (33). In BALB/c fibroblasts, IGF-I participates asa progressionfactor in cell cycle regulation in conjunction with competence factors such as EGF or FGF (34). Thus, cooperation with other growth regulatory agents is a significant feature in IGF-I action. Interplay among GH, IGF-I, and thyroid hormone has been suggestedin the induction of the gene for cytochrome P45OIIC12 in rat hepatocytes, which occurs after 2-4 h of treatment with bovine GH (35). The complex interplay suggested was that thyroid hormone potentiated GH-induced IGF-I expression, which, in turn, led to an increase in GH receptors and potentiation of GH-induced expression of P45OIIC2 and IGF-I genes.Protein kinase C appears to play a permissive role in the GH-mediated induction of these genes (36). It is conceivable that analogous complexity in interactions among GH, IGF-I, and other agents also occurs in 3T3-F442A cells. Induction of c-fos expression could be one focus for such interplay, since Fos is thought to be a component of signal transduction mechanisms for many growth factors (37). The hepatocytes in which such interplay has been examined differ from 3T3-F442A cells in at least one important regard, however, since the expressionor production of IGF-I is stimulated by GH in the hepatocytes (35), but not in 3T3-F442A cells. This suggeststhat interplay between GH and IGF-I is likely to differ in the two cell types. Furthermore, interactions between GH and IGF-I differ in the regulation of c-fos and c-jun transcription. This is consistent with previous observations that regulation by GH of c-fos and c-jun mRNA involves different mechanisms(12). General features of GH and growth factor synergism

Other growth factors that induce c-fos expression also synergize with GH to varying extents. Insulin, which probably acts through IGF-I receptors in 3T3-F442A preadipocytes, and FGF were each more effective in the presence of GH. In contrast, the interaction between GH and EGF or PDGF was additive. Occasionally, but not consistently, PDGF and GH appeared synergistic at someconcentrations. The pattern of interaction between GH and PDGF differed from the dose-related synergism between GH and IGF-I, suggestingthat the mechanismof interaction between IGF-I

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1920

GH AND

GROWTH

FACTORS

and GH is different from the interaction of PDGF with GH. It is not clear how these early interactions of GH and PDGF or FGF relate to observations that PDGF and FGF inhibit the differentiation-promoting activity of GH or serum (38, 39). Taken together, however, these studies indicate that GH interacts with growth factors early in its action and suggest that a general feature of GH action may be its interaction early in the pathway(s) by which other growth-regulating agents modulate cells. Such interactions could occur at many levels, including membrane receptors. While GH binding to its receptors on adipocytes is not competed by IGF-I or insulin (Schwartz, J., unpublished observations) (40), and GH does not alter insulin binding to adipocytes (41), GH has been observed in a preliminary report to enhance muscle IGF-I receptor mRNA levels (42). GH is known to increase levels of EGF receptors and corresponding mRNA in hepatocytes after 5 days of treatment (43); in the present study synergism between GH and EGF was not observed in 30 min. Regulation of IGF-I action might also involve regulation of IGF-binding proteins. For example, in osteoblasts, potentiation of IGF-I action by GH correlated with the presence of IGF-binding protein-3 (44). Mechanisms of action of GH and other growth factors that regulate c-fos expression share common features, including receptor-associated tyrosine kinase activity and involvement of diacyl glycerol, protein kinase C, or calcium in signal transduction (45-50). These signal transduction pathways are known to converge (51), and the effects of growth factors could potentially intersect at any of these levels. At present, it is not possible to determine where such interactions occur in the pathway for GH-induced differentiation of 3T3-F442A cells. Thus, although all of the individual steps have not yet been delineated, the early interactions between GH and other growth factors in 3T3-F442A cells suggest a generalized mechanism in which a major contribution of GH to cellular growth regulation is to synergize with specific growth-promoting signals early in transduction of such signals in target cells, resulting in enhanced gene transcription. Acknowledgments The authors acknowledge the excellent assistance Stephenson, and thank L. Argetsinger, C. Carter-%, reviewing the manuscript.

provided by E. W. and A. King for

References 1. Scow RO, Wagner EM, Ronow E 1958 Effect of growth hormone and insulin on body weight and nitrogen retention in pancreatectomized rats. Endocrinology 62:593-599 2. Salmon Jr WD, Daughaday WH 1957 A hormonally controlled serum factor which strmulat& sulfate incorporation by cartilage in vituo. 1 Lab Clin Med 49:825-836 OGP, Eden S, Jansson J-O 1985 Mode of action of 3. Isaksson pituitary growth hormone on target cells. Annu Rev Physiol47:483499 4. Goodman HM, Schwartz J 1974 Growth hormone and lipid metabolism. In: Sawyer W, Knobil E (eds) Handbook of Physiology, sect 7, vol 4, part 2. American Physiological Society, Washington DC, pp 211-231 5. Morikawa M, Nixon T, Green H 1982 Growth hormone and the

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IN INDUCING

c-fos

Endo. Vol131.

1992 No 4

adipose conversion of 3T3 cells. Cell 29:783-789 6. Nixon T, Green H 1984 Contribution of growth hormone to the adipogenic activity of serum. Endocrinology 14:527-532 7. Nixon T, Green H 1984 Growth hormone promotes the differentiation of myoblasts and preadipocytes generated by azacytidine treatment of 10T,,~ cells. Proc Nat1 Acad Sci USA 81:3429-3432 8. Green H, Morikawa M, Nixon T 1985 A dual effector theory of growth hormone action. Differentiation 29:195-198 9. Doglio A, Dani C, Grimaldi I’, Ailhaud G 1986 Growth hormone regulation of the expression of differentiation-dependent genes in preadipocyte Ob1771 cells. Biochem J 238:123-129 10. Guller S. Sonenberg M. Corin RE 1989 Expression of growth hormone:independeG adipogenesis by a 3T3 cell variant. Endocrinology 124:325-332 11. Lindahl A, Isgaard J, Carlsson L, Isaksson OGP 1987 Differential effects of growth hormone and insulin-like growth factor-l on colony formation of epiphyseal chondrocytes in suspension culture in rats of different ages. Endocrinology 121:1061-1069 12. Gurland G, Ashcom G, Cochran BH, Schwartz J 1990 Rapid events in growth hormone action. Induction of c-fos and c-jun transcription in 3T3-F442A preadipocytes. Endocrinology 127:3187-3195 13. Schwartz J 1984 Growth hormone directly alters glucose utilization in 3T3 adipocytes. Biochem Biophys Res Commun 125:237-243 14. Rollins BJ, Stiles CD 1989 Serum-inducible genes. Adv Cancer Res 53:1-32 15. Bravo R 1990 Genes induced during the GO/G1 transition in mouse fibroblasts. Semin Cancer Biol 1:37-46 16. Muller R 1986 Cellular and viral fos eenes: structure, regulation of expression and biological propeities of their encoded- products. Biochim Biophys Acta 823:207-225 17. Rauscher III FJ, Sambucetti LC, Curran T, Distel RJ, Spiegelman BM 1988 Common DNA binding site for Fos protein complexes and transcription factor AI’-I. Cell 5%471-480 18. Suieaelman B. Distel RI. Ro H-S. Rosen BS. Satterberg B 1988 fos p;otioncogene and the regulation of gene expression in adipocyte differentiation. J Cell Biol 107:829-832 19. Slootweg MC, deGroot RI’, Herrmann-Erlee MPM, Koornneef I, Kruijer W, Kramer Y M 1991 Growth hormone induces expression of c-jun and jun B oncogenes and employs a protein kinase C signal transduction pathway for the induction of c-fos oncogene expression. Mol Endocrinol 6:179-188 20. Doglio A, Dani C, Grimaldi I’, Ailhaud G 1989 Growth hormone stimulates c-fos gene expression by means of protein kinase C without increasing inositol lipid turnover. Proc Nat1 Acad Sci USA 86:1148-1152 21. Rymaszewski Z, Cohen RM, Chomczynski P 1991 Human growth hormone stimulates proliferation of human retinal microvascular endothelial cells in vitro. Proc Nat1 Acad Sci USA 88:617-621 22 Zezulak KM, Green H 1986 The generation of insulin-like growth factor I-sensitive cells by growth hormone action. Science 233:551553 23 Cochran BH 1983 The molecular action of platelet-derived growth factor. Adv Cancer Res 45:183-216 24. Distel R, Ro HS, Rosen BS, Groves D, Spiegelman BM 1987 Nucleoprotein complexes that regulate gene expression in adipocyte differentiation: direct participation of c-fos. Cell 49:835-844 25. Guller S, Corin RE, Mynarcik DC, London BM, Sonenberg M 1988 Role of insulin in growth hormone stimulated 3T3 cell adipogenesis. Endocrinology 122:2084-2090 26. Doglio A, Dani C, Fredrikson G, Grimaldi I’, Ailhaud G 1987 Acute regulation of insulin-like growth factor-I gene expression by growth hormone during adipose cell differentiation. EMBO J 6:4011-4016 27. Mathews LS, Norstedt G, Palmiter RD 1986 Regulation of insulinlike growth factor I eene exoression bv erowth hormone. Proc Nat1 ’ ” AcadvSci USA 83:9323-9343 28. Adashi EY, Resnick CE, Svoboda ME, VanWyk JJ 1986 Somatomedin-C as an amplifier of follicle-stimulating hormone action: enhanced accumulation of adenosine 3’,5’-monophosphate, Endocrinology 118:149-155 29. Tramontano D, Cushing GW, Moses AW, Ingbar SH 1986 Insulinlike growth factor-I stimulates the growth of rat thyroid cells in ”

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GH AND culture and synergizes by TSH and Graves’-IgG.

GROWTH

FACTORS

the stimulation Endocrinology

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Growth hormone synergizes with serum growth factors in inducing c-fos transcription in 3T3-F442A cells.

GH is a major regulator of growth and metabolism, but cellular effects of GH alone have been difficult to demonstrate. Accordingly, suggestions have a...
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