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. 2011 Mar-Apr;2(2):89–94. doi: 10.4161/sgtp.2.2.15310

Characterization of ATF2 in Rel/NFκB oncogenesis reveals its role in the regulation of Ras signaling

Andrew S Liss 1,†, Henry R Bose 1,✉
PMCID: PMC3136910  PMID: 21776408

Abstract

The v-Rel oncoprotein is the acutely transforming member of the Rel/NFκB family of transcription factors. v-Rel transforms cells through the inappropriate activation and suppression of genes normally regulated by cellular Rel/NFκB family members. We have recently demonstrated that activation of Ha-Ras by v-Rel contributes to transformation. Characterization of AP-1 family members in v-Rel-mediated transformation revealed ectopic expression of ATF2 inhibited transformation by blocking Ha-Ras activity. This lack of Ha-Ras activity prevented downstream activation of the Raf-MEK-ERK pathway, a critical pathway for v-Rel-mediated transformation. Microarray analysis of cells treated with an inhibitor to the ERK pathway revealed a relatively small number of genes that are specifically regulated by ERK activity in cells expressing v-Rel. These studies suggest the main contribution of ERK activity is to temper the expression of genes in v-Rel transformed cells. The mechanism by which ATF2 regulates Ras-Raf-MEK-ERK signaling appears to be a context dependent event. The ectopic expression of ATF2 in cells that are not expressing v-Rel results in the activation of Ha-Ras. However, activation of downstream Raf-MEK-ERK signaling pathway is blocked, likely through the recruitment of inhibitory 14-3-3 proteins to c-Raf. These results suggest a diverse role for ATF2 in the regulation of the Ras-Raf-MEK-ERK pathway.

Key words: v-Rel, NFκB, ATF2, Ras, MAPK, ERK, c-Raf

The oncogenic transformation of cells often occurs through the inappropriate activity of signaling cascades and transcription factors. For the last decade and a half work by our group has focused on identifying the mechanisms by which Rel/NFκB proteins contribute to oncogenesis. In this article we review our recent study (Oncogene 2010; 29:4925–37) that characterized the altered activity of Ha-Ras and its downstream Raf-MEK-ERK pathway in response to v-Rel, an oncogenic Rel/NFκB protein and ATF2, a member of the AP-1 family of transcription factors. While the activation of the Ras-Raf-MEK-ERK pathway by v-Rel is a key step for transformation, ATF2 has promoting and inhibitory effects on Ha-Ras activity in a context dependent manner.

Altered Rel/NFκB and AP-1 Activity in Oncogenesis

The Rel/NFκB family of transcription factors mediates diverse cellular programs including proliferation, apoptosis, immune and inflammatory responses. Members of the vertebrate family include c-Rel, NFκB1, NFκB2, RelA (p65) and RelB. In unstimulated cells, Rel/NFκB dimers are retained in the cytoplasm through association with IκB proteins. Upon stimulation by a wide variety of extra cellular signals, IκB kinases (IKKs) are activated to rapidly phosphorylate IκB proteins. Phosphorylation of IκBs mark them for ubiquitination and subsequent proteasomal degradation.1 Rel/NFκB complexes released of IκB inhibition translocate to the nucleus where they bind to specific decameric DNA sites (κB sites) to regulate the expression of a wide range of target genes, including ikba.2 Thus, the activation of the Rel/NFκB pathway results in the re-expression of inhibitory proteins necessary to restore the basal level of NFκB activity in normal cells and ensure the transient activation of these proteins.

Inappropriate regulation of the Rel/NFκB network can promote the malignant transformation of cells. Elevated expression of Rel/NFκB proteins and/or disruption in IKK/IκB regulation has been linked to several different types of solid cancers as well as cancers of hematopoietic origin.3,4 The first evidence of a role for Rel/NFκB proteins in oncogenic cell transformation resulted from studies with v-rel. The v-rel oncogene was derived by a nonhomologous recombination event between the turkey c-rel proto-oncogene and an avian retrovirus. v-Rel has acquired multiple mutations that alter its DNA binding specificity and transactivation potential relative to c-Rel. These mutations also render v-Rel less sensitive to IκB inhibition allowing for its constitutive nuclear access in the absence of an appropriate exogenous signal. The cumulative effects of these mutations account for the strong oncogenic potential of v-Rel.5

v-Rel efficiently transforms murine and avian cells of hematopoietic origin as well as avian embryonic fibroblasts. The ability of v-Rel to transform these cells is characterized by their abilities to form colonies in soft agar and/or induce tumors in vivo. Transformation by v-Rel is mediated by the inappropriate activation or suppression of genes which are normally regulated by Rel/NFκB proteins. Work by our group has focused on identifying genes that exhibit altered expression in response to v-Rel, and characterizing the contribution of these genes to v-Rel-mediated transformation. Many of the v-Rel target genes that we have characterized have also been implicated in human malignancies. These genes include the inhibitor of apoptosis ch-IAP1, the transcription factor IRF4, a component of telomerase TERT and the GTPase TC10.6–9 Recently we have demonstrated that activity of another GTPase, Ha-Ras is induced by v-Rel and plays a significant role in transformation.10 Our previous studies have also characterized the altered expression of AP-1 family members in v-Rel transformed cells and the role of AP-1 proteins to v-Rel-mediated transformation has been of interest to our group for quite some time.10,11 Similar to Rel/NFκB proteins, AP-1 proteins are a family of transcription factors that regulate cell proliferation, differentiation and apoptosis in response to external stimuli.12 This family of transcription factors is composed of proteins from the Fos, Jun and ATF families of leucine zipper containing proteins. Although, identified as viral oncoproteins, Jun and Fos have been found to be associated with cell transformation either through their overexpression or their cooperation with other oncoproteins.13–15 Our work defining the importance of the elevated expression of c-Jun and c-Fos to v-Rel mediated transformation adds to body of evidence implicating the activity of these proteins in a wide variety of oncogenic pathways.10

In contrast, the role of ATF2 in oncogenesis is not well defined. There are conflicting results in the literature that suggest a complex role for ATF2 in cancer. Ectopic expression of ATF2 has been found to enhance proliferation in a variety of human and mouse cancer cell lines.16,17 Similarly, elevated expression of ATF2 is implicated in prostate and breast cancer.18 However, other studies have demonstrated that reduced ATF2 expression predisposed mice to mammary tumors and the development papillomas.18–20 Similarly, our own studies suggest a tumor promoting and suppressing role for ATF2.10 Consistent with the elevated expression of ATF2 observed in v-Rel-expressing cells, reducing ATF2 expression by shRNA decreased the transformation potential of v-Rel. However, ectopic expression of ATF2 with v-Rel reduced its transformation potential.

ATF2 Alters the Activity of the Ras-Raf-MEK-ERK Pathway

To try to understand the mechanism by which ATF2 inhibited v-Rel-mediated transformation we looked at whether the overexpressed ATF2 protein was properly activated by its upstream kinase pathway. The activity of ATF2 is regulated, at least in part, by mitogen-activated protein kinases (MAPKs) which phosphorylate ATF2 at Thr69 and Thr71. Depending on the stimuli, ATF2 is activated by one or more members of the MAPK family. In response to cell stresses, such as DNA damage-inducing agents, the p38 or JNK MAPKs directly phosphorylate Thr69 and Thr71 of ATF2.21,22 However, in response to growth factor stimulation, ATF2 is activated by a two-step mechanism involving both p38 and ERK MAPK pathway.23 The initial phosphorylation of Thr71 results from the activation of the Ras-Raf-MEK-ERK pathway, and the proceeding phosphorylation of Thr69 occurs via the activation of the Ras-Ral-RalGDS-Src-p38 pathway. In our study, we observed an elevated level of phosphorylated ATF2 at Thr69 and Thr71 in cells overexpressing ATF2 which was solely dependent on the activity of p38MAPK.10

Interestingly, our characterization of the MAPK pathways that influence ATF2 activity, revealed a role for ATF2 in the regulation of ERK (summarized in Table 1).10 In cells ectopically expressing ATF2, the level of active ERK was reduced. We speculated that the ability of ATF2 to alter ERK activity may contribute to the inhibition of transformation by v-Rel. Although not previously described for v-Rel, ERK has a well-defined role in promoting the malignant transformation of cells. Evaluation of the ERK pathway revealed that v-Rel induces Ha-Ras activity which results in the activation of the Raf-MEK-ERK signaling cascade. More recent work from our group demonstrated that direct inhibition of ERK activity suppresses transformation by v-Rel, defining the critical nature of this pathway to v-Rel-mediated transformation.24 Interrogation of the effects of ectopic expression of ATF2 in v-Rel expressing cells revealed that ATF2 blocks v-Rel induced activation of ERK and this inhibition of ERK activity resulted from a block in Ha-Ras activation.

Table 1.

Effects of v-Rel and ATF2 on Ha-Ras signaling and transformation

Expressed gene Ha-Ras activity Raf/MEK/ERK signaling c-Raf p-Ser259 Transformation
v-Rel Enhanced Enhanced Reduced Enhanced
v-Rel and ATF2 Reduced Reduced Reduced Reduced
ATF2 Enhanced Reduced Enhanced No change
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The regulation of Ha-Ras and ERK activity by ATF2 is complex and a context dependent process. In contrast to cells co-expressing v-Rel, the ectopic expression of ATF2 alone in the DT40 B-cell line resulted in the activation of Ha-Ras and the downstream signaling component, c-Raf (phosphorylation of serine 338).10 Despite the activation of these components, decreased levels of active phosphorylated MEK1/2 and ERK were observed. A more in depth analysis of c-Raf revealed that elevated levels of c-Raf phosphorylated at serine 259 were found in DT40 cells ectopically expressing ATF2. The phosphorylation of c-Raf at serine 259 has been shown to block downstream signaling by recruitment of 14-3-3 inhibitory proteins.25,26 This inhibitory phosphorylation at serine 259 appears to supersede the function of the activating phosphorylation at serine 338, as further downstream signaling was not observed. Although binding of 14-3-3 to c-Raf phosphorylated on serine 259 in DT40 cells ectopically expressing ATF2 conforms to our model, experiments demonstrating this direct interaction have not been performed. The experiments in DT40 cells revealed two unique observations. First, ATF2 expression alone can activate Ha-Ras. This is in contrast to the inhibition of v-Rel induced activation of Ha-Ras by ATF2 we observed previously. Secondly, ectopic expression of ATF2 can inhibit Ha-Ras signaling by inducing the phosphorylation of an inhibitory serine on c-Raf. Both of these events appear to be cell type and/or context dependent. We have not observed any evidence for the induction of Ha-Ras or c-Raf serine 259 phosphorylation in embryonic fibroblast cultures. Although this suggests a cell type specific effect, DT40 cells are transformed by the insertional activation of c-myc by avian leukosis virus and therefore the differences observed in the presence and absence of v-Rel may at least in part be due to cooperative events of the myc pathway.

Given the broad role for ATF2 in gene regulation, there are likely additional pathways that are being altered by ATF2 to affect transformation by v-Rel. However, it is enticing to speculate that the ability of ATF2 to regulate the Ras-Raf-MEK-ERK signaling pathway explains the observed decrease in the transformation potential of v-Rel when the expression of ATF2 was either increased or decreased. As discussed earlier, ectopic expression of ATF2 inhibited v-Rel-mediated activation of Ha-Ras. Additionally, we observed a corresponding activation of Raf-MEK-ERK pathway activation upon knockdown of ATF2 expression. These results fit nicely with our recent report of a “Goldilocks effect” of ERK activation on v-Rel-mediated transformation.24 The use of dominant negative mutants and siRNAs demonstrated that the activation of ERK is critical for transformation by v-Rel. However, additional activation of this pathway beyond an optimal range results in the inhibition of transformation.

The mechanism by which ATF2 inhibits the activation of Ha-Ras is not understood. The role for ATF2 in gene regulation would suggest that its overexpression results in the activation of an inhibitor of Ha-Ras or the downregulation of a component of the upstream signaling pathway. A recent study characterizing the role of ATF2 in skin carcinogenesis reported the elevated expression of EGFR in ATF2 deficient cells.19 The EGF signaling pathway is a well characterized activator of Ha-Ras and the potential for ATF2 suppressing EGFR expression may, in part, account for its inhibitory effects on v-Rel mediated transformation. However, given the ability of ATF2 to induce Ha-Ras activity in DT40 cells lacking v-Rel suggests the mechanism by which ATF2 regulates Ha-Ras signaling is complex.

Identification of Genes Affected by Inhibition of Ras-MEK-ERK Pathway

To gain insight into the mechanism by which the inhibition of the Ras-MEK-ERK pathway by ATF2 inhibits v-Rel-mediated transformation we performed microarray analysis. Since the main function of ATF2 is to regulate gene expression, microarray analysis of cells ectopically expressing ATF2 would likely identify many genes unrelated to its inhibition of the Ras-MEK-ERK pathway. To focus our results on this aspect of ATF2, we chose to utilize pharmacological inhibition of the ERK pathway. DT40 cells exhibit enhanced ability to form colonies in soft agar upon expression of v-Rel and inhibition of the ERK pathway reduces the ability of v-Rel expressing DT40 cells to form colonies to levels observed in control cells.24 Importantly, inhibition of ERK activity had no effect on the ability of control cells to from colonies in soft agar. Thus, DT40 cells provide a valuable system to evaluate the mechanism by which the inhibition of ERK activity inhibits v-Rel-mediated transformation.

Microarray analysis of v-Rel expressing DT40 cells treated with an inhibitor to MEK1/2, the immediate upstream activator of ERK identified sixty-seven genes with altered expression (Fig. 1). The expression of one of these, SNAI2, has previously been demonstrated to be induced by ERK upon EGFR stimulation.27 EGFR activation of ERK is one of the best characterized Ras-Raf-MEK pathways and the identification of a downstream response of this pathway suggests that these experiments are likely to identify genes affected by inhibition of Ras-Raf-MEK-ERK by ATF2.

Figure 1.

Figure 1

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Identification of ERK-regulated genes in v-Rel expressing cells. DT40 cells infected with control viruses or those expressing v-Rel were exposed to the MEK1/2 inhibitor U0126 or the negative control U0124. Twelve hours later, cells were harvested and RNA isolated for microarray experiments utilizing the Chicken 13K array. The expression of genes in cells treated with U0126 relative to U0124 was determined. Only those genes that returned data from at least two of three independent experiments were included in this analysis. Statistical analysis was performed using Significance Analysis of Microarrays (SAM). Listed genes were induced by at least two-fold, or suppressed by at least 1.7-fold in v-Rel expressing cells, but not in control cells. The average change in expression of genes is shown for each gene. For genes that were downregulatred by ERK pathway inhibition, the reciprocal of the fold-change is reported. The corresponding SAM-derived q-value for each change in gene expression is also shown. cDNAs on the Chicken 13K array that do not correspond to know coding genes are noted (‡).

Since ERK has a well known role in activating a variety of transcription factors we expected to observe a large number of genes with reduced expression upon ERK inhibition. Surprisingly, only five genes were identified with reduced expression. One possible explanation for the limited number of these genes is that the inhibition of the ERK pathway was for a relatively short period of time and many ERK regulated genes may encode more stable mRNAs.

While only a few genes were downregulated after ERK inhibition, 62 genes were upregulated at least two-fold in v-Rel expressing cells. Most of these genes fall into four major catagories: transcriptional regulators, RNA binding/regulators of splicing, mitochondrial proteins and components of the ubiquitin pathway. Among the genes suppressed by ERK activity, a number of candidates can be found whose expression may be detrimental to v-Rel-mediated transformation. Inactivation of salt-inducible kinase-1 (SIK1) has been shown to inhibit p53 activity and allow cells to grow in an anchorage-independent manner.28 Deletion of SIK1 also promotes metastasis in vivo. UPF1 is a known regulator of non-sense mediated decay, including alternatively spliced variants of TERT.29 The downregulation of this gene by ERK may help explain the relatively high levels of non-coding alternatively spliced TERT variants in v-Rel transformed cells. STAG2 has been demonstrated to interact with and cooperate with RelA in NFκB mediated transcriptional regulation.30 Interestingly, nuclear localization of RelA is not observed in v-Rel transformed cells and the altered expression of this gene may contribute to the altered NFκB program established by v-Rel. A particular interesting gene is PARC2. This gene shares a bidirectional promoter with PARK2 and these genes are transcriptionally co-regulated. PARK2 is a familial Parkinson disease gene and its deletion/inactivation has been reported in a variety of cancers, including those linked to Rel/NFκB.31 Although altered PARK2 expression was not identified in these experiments, further investigation is warranted.

The results of our studies suggest a model for the diverse regulation of Ha-Ras signaling by ATF2 (Fig. 2). v-Rel transforms cells in part through the induction of Ha-Ras. Although the mechanism by which v-Rel activates Ha-Ras is unknown, it likely involves the induction of growth factors. The activation of Ha-Ras leads to the specific activation of the Raf-MEK-ERK signaling pathway, largely resulting in the negative regulation of gene expression. The ectopic expression of ATF2 with v-Rel blocks v-Rel-mediated Ha-Ras activation. However, the regulation of Ha-Ras by ATF2 is context dependent. The extropic expression of ATF2 in the absence of v-Rel results in the activation of Ha-Ras. In spite of this, Raf-MEK-ERK signaling does not occur, as ATF2 likely induces the recruitment of inhibitory 14-3-3 proteins to c-Raf. Further investigation of the effects on Ha-Ras signaling is required to determine whether Ha-Ras activation by ATF2 results in the activation of other downstream signaling pathways.

Figure 2.

Figure 2

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Proposed model of ATF2 regulation of Ha-Ras signaling. (A) Activation of Ras-Raf-MEK-ERK signaling by v-Rel. The expression of v-Rel in fibroblast and lymphoid cells results in the induction of Ha-Ras activity. Activated Ha-Ras leads to the phosphorylation and activation of c-Raf (serine 338) and subsequent activation of MEK1/2 and ERK. The activation of ERK by this signaling cascade leads to the altered expression of a variety of genes. (B) ATF2 blocks Ha-Ras activation by v-Rel. The ectopic expression of ATF2 with v-Rel blocks v-Rel-mediated activation of Ha-Ras and the downstream Raf-MEK-ERK pathway. (C) The ectopic expression of ATF2 alone in DT40 cells has multiple effects on Ha-Ras signaling. Ectopically expressed ATF2 is phosphorylated and activated by p38MAPK resulting in the induction of Ha-Ras activity. However, the activation of the downstream Raf-MEK-ERK pathway is blocked by phosphorylation of c-Raf at serine 259, which likely allows for binding of the inhibitory protein 14-3-3.

Extra View to: Liss AS, Tiwari R, Kralova J, Bose HR., Jr Cell transformation by v-Rel reveals distinct roles of AP-1 family members in Rel/NF-kappaB oncogenesis. Oncogene. 2010;29:4925–4937. doi: 10.1038/onc.2010.239.

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