Polyamine Dependent Early Cellular Signals and Cell Proliferation

Stina M. Oredsson

1. Introduction

When a resting cell is awakened to enter the cell cycle by mitogenic stimulation, a complex molecular machinery involving positive and negative regulation of cell-cycle progression is initiated. Part of the machinery is quite well-known. It involves receptors of various kinds, protein interactions, phosphorylation reactions, and molecular cascades carrying the signal to enter the cell cycle from the cell surface to the nucleus. In the nucleus, transcriptional activation results in an increased involvement of genes in the process. In the cytoplasm, translational and posttranslational mechanisms also have a part in the process. In this complex partly known molecular machinery, there are also molecules that not yet have been assigned a specific role; however, there are enough data to state that their role in normal cell-cycle progression is ubiquitous. The level of the polyamines—putrescine, spermidine, and spermine—are low in nonproliferating cells, but their levels increase early after mitogenic stimulation and these increases are necessary for normal rates of cell-cycle progression (1,2). In this chapter, the focus will be on the role of polyamines in early signaling processes that are required for normal cell-cycle progression.

2. Mitogenically Activated Signal Transduction Pathways

Signal transduction is the process by which information from an extracellular signal is transmitted from the plasma membrane into the cell and along an intracellular chain of signaling molecules to stimulate a cellular response. Mitogenic stimulation, when a growth factor binds to its receptor on the cell surface, is such a process. This stimulation initiates a number of parallel signal transduction pathways, the combined role of which is to achieve a balanced regulation of the initiated signal.

Mitogenic stimuli initiate cell proliferation via different classes of cell surface receptors, which include growth factor receptor tyrosine kinases and G protein-coupled receptors. This results in tyrosine phosphorylation of Shc and the sequential activation

From: Polyamine Cell Signaling: Physiology Pharmacology and Cancer Research Edited by: J.-Y. Wang and R. A. Casero, Jr. © Humana Press Inc., Totowa, NJ

Activated Ras

Fig. 1. Schematic representation of Ras-activated signal transduction pathways. The three-tiered MAPK pathways JNK/SAPK, p38, and Erk 1/2 are shown where MAPKKK, MAPKK, and MAPK show the first, second, and third phosphorylation levels, respectively. Ras also activates phosphatidylinositol 3-kinase (PI3K)-mediated and Ral guanine-nucleotide-exchange factor (GDS)-mediated signals (Ral-GDS). Ras denotes a superfamily of small GTPases.

Fig. 1. Schematic representation of Ras-activated signal transduction pathways. The three-tiered MAPK pathways JNK/SAPK, p38, and Erk 1/2 are shown where MAPKKK, MAPKK, and MAPK show the first, second, and third phosphorylation levels, respectively. Ras also activates phosphatidylinositol 3-kinase (PI3K)-mediated and Ral guanine-nucleotide-exchange factor (GDS)-mediated signals (Ral-GDS). Ras denotes a superfamily of small GTPases.

of Grb2, SOS, and then Ras (3,4) (Fig. 1). Ras activity is controlled by a regulated guanosine 5'-diphosphate/guanosine 5'-triphosphate cycle where only guanosine 5'-triphosphate-bound Ras is active. The Shc/Grb2/SOS complex stimulates the formation of active guanosine 5'-triphosphate-Ras from inactive guanosine 5'-diphosphate-Ras. Here Ras denotes a superfamily of small guanosine 5'-triphosphatases of more than 80 mammalian members. The prototypic Ras proteins are H-Ras, K-Ras, and N-Ras. Ras activation then results in the activation of the ERK1/2 (p42/44) mitogen-activated protein kinase (MAPK pathway) through Raf. Ras-mediated activation of Raf is a complex, multistep process (3). Phosphorylated ERK1 (p44) and 2 (p42) then enter the cell nucleus and activate a variety of substrates that include the Elk-1, Egr-1, c-Jun, and c-Myc transcription factors. One of the transcriptional targets of c-Myc is ornithine decarboxylase (ODC), the initial enzymatic step in polyamine biosynthesis (5). Thus the major role of the ERK1/2 pathway is transcriptional activation. The ERK1/2 pathway is the classical three-tiered MAPK pathway where kinase phosphorylation takes place at three levels (Fig. 1).

In addition to activation of the ERK1/2 MAPK pathway, Ras activation also initiates a number of other Raf-independent signal transduction pathways (3,6). Such pathways are phosphatidylinositol 3-kinase (PI3K)-mediated and Ral guanine-nucleotide-exchange factor (GDS)-mediated signals. Ras binds to and activates the catalytic sub-

unit of PI3K, a lipid kinase. This results in the formation of phosphatidylinositol 3,4,5-triphosphate, a second messenger, that, via the phosphoinositide-dependent kinase 1, results in the activation of the protein kinase B/Akt pathway. Protein kinase B/Akt phosphorylates many proteins involved in cell-cycle progression (7,8). One of the master regulators of translational control is the target of rapamycin (TOR) protein, which controls the translational apparatus through protein phosphorylation (6). The key regulators of translation that are controlled by TOR include the p70 ribosomal S6 kinases (S6K1 and S6K2) and 4E-BP1. The TOR-S6K pathway is regulated by signals that are transmitted in response to mitogenic stimulation through PI3K. Phosphatidylinositol 3,4,5-triphosphate also contributes to the activation of the ERK1/2 pathway (6). Ral-GDS activates Ral, which has a role in both transcriptional and translational activation of cell-cycle regulatory proteins (6).

Besides the classic ERK1/2 MAPK cascade, there are two other three-tiered MAPK pathways, the C-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) MAPK and the p38 MAPK pathways (Fig. 1). These are also not only activated by growth factors, but also by other kinds of stimuli such as ultraviolet-, heat shock-, and high osmosis-induced stress (3,9). Ras activation is also important for the JNK/SAPK and p38 MAPK pathways; however, they are Raf-independent pathways as are the PI3K and Ral-DGS pathways mentioned previously. The p38 MAPK pathway has been implicated as an important negative regulator of cell-cycle progression (10). Activation of the p38 MAPK pathway results in regulation of both transcription and translation of a number of genes involved in the negative control of cell-cycle progression, but also in the stimulation of proteasome-dependent degradation of proteins that stimulate cell-cycle progression. A major target of the JNK/SAPK signaling pathway is the activation of the AP-1 transcription factor that in part is mediated by the phosphorylation of c-Jun

(11). The three-tiered kinase ladders of the JNK/SAPK and p38 MAPK pathways involve more kinases than the ERK1/2 MAPK pathway (9).

In view of its very central role in signal transduction, it is not surprising that Ras family proteins are oncogenes belonging to a family of structurally similar oncogenic proteins (6,12). Closely related to the Ras family proteins are the Rho family proteins

(12). The Rho family proteins are regulators of actin organization, gene expression, and cell-cycle progression and have been implicated to have a role in Ras-mediated transformation in the JNK/SAPK and p38 MAPK pathways. Ras initiates the cell cycle through MAPK pathways and other pathways, but subsequent action of the Rho family is required for completion of the process.

Characteristic for these pathways is that they do not function on their own. There is extensive cross talk making it difficult to study the role of a single pathway in cell-cycle regulation. In addition, there are other signal transduction pathways, such as the cytokine-stimulated pathways and the transforming growth factor (TGF)-P pathway (13,14). The specific cellular response is the sum of the total contribution of the individual pathways. Is there a place for the polyamines in this complex pattern making it even more complex? There are several studies of the role of polyamines in signal trans-duction that implicate that they have a function. The studies are of two major kinds. In many of the early studies, cells were depleted of their polyamines and the downstream appearance of transcription factors was studied. The transcription factors studied were c-Jun, c-Fos, Egr-1, and c-Myc, all dependent on the described pathways. In later studies, the specific activation of the MAPK pathways and other pathways has been studied in relation to activation of polyamine biosynthesis.

3. Polyamine Depletion and the Expression of Transcription Factors

In many of the early articles pointing to a role of polyamines in signal transduction, the cells were depleted of their polyamines by treatment with a-difluoromethyl-ornithine (DFMO) (15). DFMO is an enzyme-activated irreversible inhibitor of ODC. DFMO treatment results in the depletion of putrescine and spermidine, whereas sper-mine essentially remains unchanged.

A significant decrease in the steady-state levels of one or more of the transcription factors c-myc, c-fos, and c-jun messenger RNA (mRNA) was found in the human colon carcinoma cell line COLO320 (16) and in the rat intestinal epithelial cell line IEC-6 (17,18) after DFMO treatment. There was not a decrease in general mRNA expression pointing to a specific role for polyamines regarding c-myc and c-jun mRNA expression. Nuclear run-on assays showed that the basal rates of transcription of c-fos and c-myc were decreased in polyamine-depleted nuclei from IEC-6 cells (18,19). However, there was no difference in the stability (t1/2) of the c-myc and c-jun messages in control and polyamine-depleted cells (18). When DFMO-treated cells were stimulated with serum, there was no increase in the mRNA levels of the observed transcription factors (17,18). Spermidine supplementation to DFMO-treated IEC-6 cells restored c-myc and c-jun mRNA levels. It was suggested that regulation of transcription factor expression may be one of the mechanisms by which polyamines modulate cell growth.

In a model using rat kidney cells infected with a temperature-sensitive mutant of Kirsten sarcoma virus, it was shown that polyamines stimulate transcription of c-myc and c-fos and the expression was blocked by DFMO treatment (20). In another study, it was shown that DFMO-induced depletion of putrescine and spermidine in SV40-trans-formed 3T3 cells prevented c-jun mRNA induction by insulin; however, it did not affect c-jun mRNA induction by vanadate (21). Insulin and vanadate function through different signal transduction pathways: insulin requires G protein, whereas vanadate does not. Spermidine addition to the DFMO-treated cells restored the stimulating effect of insulin. Thus polyamines appeared to be required for the G protein-mediated insulin-stimulated signal but not for the vanadate-stimulated signal.

Schulze-Lohoff and colleagues (22) grew rat renal mesangial cells in the presence of DFMO for 4 d and then deprived the cells of fetal calf serum (FCS) for 2 d. The cells were then stimulated with FCS, and the mRNA levels of c-fos, c-jun, and Egr-1 were investigated. The researchers found that the expression of the genes did not increase to the same extent in polyamine-depleted cells as in control cells.

All these studies implicate a role for the polyamines in the efficient expression of the transcription factors c-fos, c-jun, c-myc, and Egr-1—all being effector molecules of MAPK signal transduction activation. In contrast to the studies mentioned, Charollais and Mester (23) found that the c-myc expression was not inhibited by polyamine deple tion and serum starvation in BALB/c-3T3 fibroblasts. In fact, both c-myc and ODC were expressed at relatively high levels in the serum-starved, polyamine-depleted cells. These cells could be stimulated to grow with nondialyzed FCS but not with dialyzed FCS that did not contain polyamines. However, a combination of epidermal growth factor, insulin, and putrescine resulted in immediate stimulation. These results imply that during 3 d of DFMO treatment and 3 d of serum starvation, the polyamine levels were depleted to such low levels that serum stimulation without putrescine had no effect (i.e., the growth-stimulating signals through various receptors were not functional despite the increased c-myc and ODC mRNA levels). In similarity with Charollais and Mester (23), we found that c-fos, c-jun, ODC, and AdoMetDC mRNA levels were higher in polyamine-depleted and serum-starved Chinese hamster ovary cells than in control cells (unpublished results, K. Alm and S. Oredsson). That polyamine depletion resulted in different effects on mRNA levels of transcription factors and polyamine biosynthetic enzymes may be a result of the different genetic lesions in the cell lines, with the tumor suppressor p53 being a possible candidate. It has been shown that cells with wild-type p53 appear to be blocked in Gj by polyamine depletion, whereas cells with mutated p53 do not show any specific cell-cycle block (24,25).

Bauer and colleagues (26) showed that inhibition of ODC and putrescine production by DFMO in rat aortic smooth muscle cells resulted in activation of the ERK1/2 MAPK pathway to promote induction of p21 and consequently inhibition of cell proliferation. Activation of ERK1/2 MAPK and induction of p21was inhibited by putrescine addition.

4. Signal Transduction Pathways and Activation of Polyamine Biosynthesis

It was noted early that ODC activity was rapidly and dramatically elevated by a variety of exogenous stimuli that were coupled to several signal transduction pathways (27-29).

The involvement of the Raf/MEK/ERK and PI3K pathways in ODC induction was shown in DFMO-resistant HL-60 cells that were stimulated to grow from quiescence (30,31). When ERK1/2 phosphorylation was inhibited, there was a reduction in the accumulation of ODC mRNA and protein; however, ODC protein turnover was hardly affected (31). Also, the involvement of Src, Ras, PI3K, and G-coupled proteins in ODC induction was shown using different inhibitors. When serum-starved human ECV304 cells were treated with histamine or adenosine triphosphate, there was a transient induction of ODC (32). The agents also provoked an increase in active phosphorylated ERK1/2 and p38 MAPKs. Specific inhibition of ERK1/2 MAPK prevented the induction of ODC, whereas specific inhibitors of p38 MAPK enhanced induction of ODC in a way that appeared dependent on ERK1/2 MAPK. It has been reported that PD98059-mediated inhibition of ERK1/2 MAPK phosphorylation prevented the expression of c-myc and c-fos (33) and the ODC activity (31). Addition of polyamines to NIH 3T3 cells reversed PD98059-mediated inhibition on MAPK phosphorylation and expression of c-myc and c-fos (33). In serum-starved NIH 3T3 fibroblasts, spermidine preferentially stimulated transcription and translation of c-myc, whereas putrescine stimulated transcription and translation of c-fos (34,35).

Several studies have shown that the ODC gene is deregulated in ras-transformed cells (36-40). ODC overproducing transfectants showed enhanced MAPK (31) and tyrosine kinase activities (41). MAPK activation has also been found in response to polyamine excess (42,43).

NIH 3T3 cells transfected with c-Ha-ras showed markedly enhanced ODC activity and ODC protein level (36). An increased ODC mRNA level as a result of an increased rate of transcription could account for this observation. The turnover rate of ODC mRNA was also decreased in transformed cells and the ODC protein was stabilized. The results suggested ODC deregulation at multiple levels in ras-oncogene-transformed cells. Similar results have been found for AdoMetDC and for ODC in H-Ras-transformed mouse 10T1/2 cells (44). Experiments using NIH 3T3 cells transfected with plasmids encoding activated mutants for H-Ras or RhoA suggested that the increase in ODC activity at least partly was through a Raf/MEK/ERK-independent pathway (39). To further delineate the role of different Ras effector pathways in ODC activation following stable ras transfection, NIH 3T3 cells were transfected with partial loss-of-function Ras mutants to selectively activate pathways downstream of Ras (40). Mutants that selectively activate signal transduction through the Raf/MEK/ERK, PI3K, and Ral-GDS pathways were used, as were selective pathway inhibitors. The results show that ODC transcription was controlled through a pathway dependent on Raf/MEK/ERK activation, whereas activation of the PI3K, Raf/MEK/ERK and p38 MAPK pathways were necessary for translational regulation of ODC. The p38 MAPK pathway had a negative role in translational regulation, whereas the other two stimulated translation. The importance of the Raf/MEK/ERK pathway in ODC activation was also shown in a transgenic mouse line overexpressing a constitutively active mutant of MEK1 driven by the keratin 14 promoter (45).

MAPK involvement in polyamine catabolism through the induction of spermine/sper-midine-A^-acetyltransferase has also been investigated (46). An activated Ki-ras was expressed in CaCo2 cells and ODC activity was increased, as has been shown by others. The cells showed decreased expression of spermine/spermidine-A1-acetyltransferase via a mechanism involving Raf/MEK/ERK-dependent downregulation of PPARy.

5. Conclusion

It is clear that stimulation of polyamine biosynthesis followed by increased polyamine levels are required for efficient cell-cycle progression after mitogenic stimulation 2,47-49). As reviewed previously, it is also clear that polyamines are required for normal expression of a number of transcription factors after mitogenic stimulation, one of which is c-Myc. Importantly, c-Myc is a transcription factor for ODC (5). It is also evident that several signal transduction pathways are involved in induction of balanced polyamine biosynthesis. Altogether, the data indicate that polyamines are required for efficient signal transduction and that ODC induction by c-Myc provides a feedback pathway to ensure that the polyamine levels are sufficiently high for efficient signal transduction (Fig. 2). Such a positive loop involving ODC/polyamines and MAPK pathways has been suggested 31,35). Thus polyamines appear to be important both in and downstream of signal trans-duction pathways. However, a necessary goal for polyamine research is to find the specific molecular targets for polyamine function in signal transduction as a final proof of concept.

Myc Signal Transduction
Fig. 2. Schematic representation of a polyamine signal transduction loop.


Supported by the Swedish Cancer Foundation; the Royal Physiographical Society in

Lund; the Mrs. Berta Kamprad Foundation; the Gunnar, Arvid, and Elisabeth Nilsson

Cancer Foundation; and the Crafoord Foundation.


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