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[Cancer Research 62, 1300-1304, March 1, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

Differential Gene Expression Profiles of Jnk1- and Jnk2-deficient Murine Fibroblast Cells1

Nanyue Chen, Qing-Bai She, Ann M. Bode and Zigang Dong2

The Hormel Institute, University of Minnesota, Austin, Minnesota 55912


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
c-Jun NH2-terminal kinase (JNK) 1 and JNK2 have been assumed to complement each other and mediate the same or similar biological functions. However, our recent reports indicated that 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced tumor development is suppressed in Jnk2 knockout mice but enhanced in Jnk1 knockout mice. In the present work, primary embryo cells were isolated from wild-type, Jnk1-/- and Jnk2-/- mice and used for cDNA microarray analysis. The patterns of gene expression in Jnk1-/-, Jnk2-/-, and wild-type cells are different. After 12-O-tetradecanoylphorbol-13-acetate treatment, the changes in the gene expression profiles in three different kinds of cells appear to agree with the differences in susceptibility to tumorigenesis of each respective animal model. These results suggest that JNK1 and JNK2 proteins have different roles in modulating cell function.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The JNKs3 belong to the MAPK family of signal transduction components that are rapidly initiated and activated by many extracellular stimuli, including interleukin 1, tumor necrotic factor, and UV irradiation (1) . JNK protein kinases are encoded by three genes, Jnk1, Jnk2, and Jnk3 (2) . JNK3 is restricted mainly to the brain, heart, and testis, and the ubiquitously expressed JNK1 and JNK2 proteins play an important role in modulation of cell function in many tissues (1 , 2) . Although studies have indicated that the substrate affinities and specificities of JNK1 and JNK2 are dissimilar, functional differences between JNK1 and JNK2 remain unclear (1 , 3) . MAPK kinase 4 and MAPK kinase 7 are upstream kinases of JNKs and activate both JNK1 and JNK2. Both JNK1 and JNK2 share the same substrates, including activating transcription factor 2 and c-Jun transcription factors (3) , and were assumed to complement each other and mediate the same or similar biological functions. Recently, the development of Jnk1 or Jnk2 knockout mice makes possible the in depth study of their functions (4 , 5) . By using these mice and a mouse multistage skin tumor model, we investigated the role of JNK1 and JNK2 in mediating 7,12-dimethylbenz(a)anthracene-initiated and TPA-promoted skin tumorigenesis. Interestingly, we found that JNK2 deficiency inhibited skin tumorigenesis (6) , whereas JNK1 deficiency resulted in a higher tumor burden (7) . These results indicate that JNK1 and JNK2 have different roles in mediating skin tumorigenesis. Thus, the identity of downstream molecules that are differentially regulated by JNK1 and JNK2 becomes an important question that needs to be addressed. To answer this interesting question, an important step was to investigate the gene expression profiles in Jnk1 or Jnk2 knockout cells. The cDNA array system is a useful and powerful tool to inspect alterations in many genes simultaneously, and the analysis of the profiles of changes in gene expression will provide information for future investigations of the function of these genes (8) .


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Materials.
DMEM, gentamicin, and FBS were from Whittaker Biosciences (Walkersville, MD); L-glutamine was from Life Technologies, Inc. (Grand Island, NY); and TPA was from Sigma Chemical Co. (St. Louis, MO). Primers for PCR and RT-PCR were synthesized by Life Technologies, Inc. The QuantumRNA ß-actin Internal Standards Kit was from Ambion Inc. (Austin, TX), the Omniscript Reverse Transcriptase Kit and HotStarTaq Master Mix Kit were from Qiagen Inc. (Valencia, CA), and the Atlas cDNA array kit was from Clontech Laboratories, Inc. (Palo Alto, CA).

Primary Embryonic Cell Preparation.
Jnk1-/- and Jnk2-/- mice were gifts from Dr. Richard Flavell, Yale University (5) . The primary embryonic cells were generated as reported (9) . In brief, the embryos were freed from surrounding membranes and minced with scissors into small pieces. Trypsin solution (5 ml) was added, and the embryos were incubated in a dish at 37°C while pipetting the digestion periodically. When the bulk of the suspension consisted of single cells and small clumps of cells, the digestion was stopped by adding 5 ml of DMEM containing 10% FBS to the digestion. The suspension was transferred to a centrifuge tube, and large chunks were allowed to settle out at room temperature. The supernatant fraction was transferred to a fresh tube and centrifuged at 3000 rpm for 10 min. The cell pellet was resuspended and plated into culture flasks at a density of 1–2 x 105 cells/cm2. DMEM with 10% FBS was added, and the cells were incubated at 37°C in a 5% CO2 atmosphere. The culture medium was changed 8–24 h after the initial plating to remove cellular debris and unattached cells. Regular culture procedures were subsequently followed as described previously (9) .

cDNA Array.
Cells were cultured in DMEM containing 10% FBS and then starved with serum-free DMEM for 24 h. Cells were harvested after a 2-h treatment with 20 ng/ml TPA. Total RNA was isolated using the Atlas Pure Total RNA Labeling System (Clontech Laboratories, Inc.) according to the manufacturer’s recommendations. Differential hybridization analysis was done using Atlas mouse cDNA expression arrays (Clontech Laboratories, Inc.). cDNA probe preparation and hybridization were done according to the manufacturer’s recommendations. The array results were scanned using the Storm 840 PhosphorImager (Molecular Dynamics, Sunnyvale, CA) and analyzed using Atlas Image 1.01 software (Clontech Laboratories, Inc.).

Cluster Analysis of the Data.
Distance measurements and hierarchical clustering computations were performed using Cluster and TreeView software.4 The basic idea of clustering is to assemble a set of items (genes or arrays) into a tree, where items are joined by very short branches if they are very similar to each other. The cluster software used currently performs three types of clustering, binary, agglomerative, and hierarchical. Hierarchical clustering is an incredibly powerful and useful method for analyzing all sorts of large genomic datasets.

Relative Quantitative RT-PCR.
Total RNA was extracted from primary embryo cells, and cDNA transcription and PCR were done using the Omniscript Reverse Transcriptase Kit and HotstarTaq Master Mix Kit (Qiagen Inc.) according to the manufacturer’s instructions. Primers used were 5'-ACATGGACACGCAAGAACGCATCA-3' and 5'-TGAGGACTTTCTGTTTGACGTGCG-3' for JunD, 5'-GTGGAGAGACAGAGGAGGAGAG-3' and 5'-CAGAGACAAGGGAATAGGAGGAG-3' for GST5-5, 5'-ACCCAGCCTTTTTCTCTTCAG-3' and 5'-GTTCTTCCGTTCTTCTTGCTTC-3' for TNFIP3, and 5'-CAGCCTCTATTCCTCATCCC-3' and 5'- GAAAGCCGAAGGAGAGAGAC-3' for vimentin. After determining the linear range of RT-PCR for each of the target genes, the optimal ratio of actin primers:competimers was measured by using the QuantumRNA ß-actin Internal Standards Kit (Ambion). The values divided the signal obtained for the gene-specific amplicon by the signal obtained for the actin amplicon.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Identification of Genomic DNA Phenotype and Protein Expression of Jnk1-/- and Jnk2-/- Primary Embryonic Cells.
The genomic DNA phenotype and protein expression of Jnk1-/- and Jnk2-/- cells were confirmed by PCR and Western blotting, respectively. In Jnk2-/- cells, a DNA fragment of 270 bp (-/-) replaced the normal fragment of 400 bp (+/+), whereas in Jnk1-/- cells a 390-bp fragment replaced the normal 460-bp fragment. JNK2-deficient (JNK2-/-) cells did not express the JNK2 protein, and JNK1-deficient cells did not express the JNK1 protein. Expression of JNK1 in Jnk2-/- cells, expression of JNK2 in Jnk1-/- cells, and expression of extracellular signal-regulated kinases were unaffected (data not shown). These results are consistent with the results obtained from Jnk1-/- or Jnk2-/- mice (6 , 7) .

Microarray Results of Gene Expression in Primary Embryonic Cells.
To determine the differences between WT, Jnk1-/-, and Jnk2-/- cells, the Atlas cDNA expression array system was used. The Mouse 1.0 version array membrane includes 558 genes, and two parallel dots for each gene guarantee the reliability and repeatability of the experiment. The array results in Fig. 1Citation show that the two dots representing almost all genes have equal density. Array data were analyzed using AtlasImage 1.01 software. Any gene showing differential expression between the two parallel dots was automatically excluded. After normalization, differences in gene expression were compared between WT and each of the other five groups, which included TPA-treated WT cells, untreated Jnk1-/- cells, TPA-treated Jnk1-/- cells, untreated Jnk2-/- cells, and TPA-treated Jnk2-/- cells.



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  		Fig. 1. cDNA microarray results. Primary embryonic cells of WT, Jnk1-/-, and Jnk2-/- mice were cultured in monolayers in 15-cm dishes (3 x 106 cells/dish) until they reached 90% confluence. The cells were then starved for 24 h in FBS-free DMEM, followed by treatment with 20 ng/ml TPA for another 2 h. RNA was extracted, and cDNA was transcribed and labeled with [32P]ATP. The hybridization was performed according to the manufacturer’s recommendations (Clontech Laboratories, Inc.). Array membranes were scanned using the Storm 840 PhosphorImager (Molecular Dynamics). The figure shows a comparison of the same area of each membrane for each of the six experimental groups, and the arrow indicates a comparison of the same gene on each membrane.

 
Cluster Analysis of Genes.
We compared gene expression among the six groups and found that the expression of 63 genes was altered in the total number of 558 genes tested. We analyzed the genes by using the Cluster and TreeView software program and found 6 groups or clusters of genes (Fig. 2)Citation . The identity and relative level of expression of the genes found in each cluster are shown in Table 1Citation . In general, the 8 genes in cluster 1 are found to be expressed mainly in Jnk2-/- cells; the 4 genes in cluster 2 are expressed mainly in Jnk2-/- and TPA-treated WT cells; the 4 genes in cluster 3 are highly expressed in TPA-treated WT and TPA-treated Jnk1-/- cells; the 14 genes in cluster 4 are expressed mainly in WT cells, Jnk1-/- cells, and TPA-treated Jnk2-/- cells; the 16 genes in cluster 5 are expressed mainly in WT cells; and the 17 genes in cluster 6 are expressed mainly in TPA-treated Jnk2-/- cells. The average density of each group in each cluster was calculated and is also shown in Table 1Citation . A greater expression level is indicated by a higher positive number.



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  		Fig. 2. Hierarchical clustering of differentially expressed genes. The array data were analyzed with AtlasImage 1.01 (Clontech Laboratories, Inc.). The results were normalized against all of the housekeeping genes according to the manufacturer’s recommendations (Clontech Laboratories, Inc.). Cluster analysis (http://rana.stanford.edu/software) revealed six groups or clusters of gene expression. C, cluster. Red indicates up-regulated genes, and green indicates down-regulated genes. Darker color signifies less change compared with lighter color.

 

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  		Table 1 The relative density of expression-differentiated genesa

 
Relative Quantitative RT-PCR Confirmed the Results from cDNA Array Analysis.
To verify the reliability of the microarray data, we measured the expression levels of several genes by using relative quantitative RT-PCR. The results in Fig. 3Citation showed that the gene expression patterns from two independent methods were similar.



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  		Fig. 3. The correlation of cDNA array and quantitative RT-PCR data. A, the original densitometer analysis of four genes from cDNA array. B, relative quantitative RT-PCR of the same genes. The values are expressed as ratios of specific genes:internal standard.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Gene Expression Profiles among Untreated WT, Jnk1-/-, and Jnk2-/- Cells Are Markedly Different.
JNKs play important roles in modulating cell proliferation, differentiation, and apoptosis, but the differences in function between JNK1 and JNK2 are not clear. We recently reported that the roles of JNK1 and JNK2 in mediating TPA-induced skin tumorigenesis are not only different but may even be opposite. To investigate the mechanism for these differences, we examined gene expression among WT, Jnk1-/-, and Jnk2-/- knockout cells and found that the gene expression profiles are different. In WT cells, 37 genes are highly expressed (Fig. 2Citation , clusters 4 and 5 and partial cluster 6; Table 1Citation ). In Jnk1-/- cells, 17 genes are highly expressed, and 14 of those genes are also highly expressed in WT cells (mainly cluster 4), suggesting that these 14 genes may not be regulated by JNK1. In addition, 3 of the 17 genes are specifically expressed in Jnk1-/- cells, which may indicate that these genes are negatively regulated by JNK1 in the normal growth situation. On the other hand, the expression of 22 genes (cluster 5 and partial cluster 6) is inhibited in both Jnk1-/- and Jnk2-/- cells compared with WT cells, indicating that these genes may be positively regulated by JNK1 as well as JNK2 in normal cells. In Jnk2-/- cells, 10 genes are highly expressed (clusters 1 and 2) compared with WT and Jnk1-/- cells, indicating that these genes are negatively regulated only by JNK2 in normal cells. The expression of 14 genes (cluster 4) is markedly inhibited in Jnk2-/- cells compared with WT and Jnk1-/- cells, suggesting that normally these genes may be positively regulated by JNK2, but not by JNK1.

Many substrates of JNK, such as activating transcription factor 2, c-Jun, and Elk, may be cell transcription factors, which regulate the expression of target genes. From the present results, the gene expression profiles are markedly different between Jnk1-/- and Jnk2-/- cells, indicating that some of substrates of JNK1 and JNK2 may also be different. Genes down-regulated specifically in Jnk1-/- or Jnk2-/- cells may possibly be related to the target genes of JNK1 or JNK2 because these genes may normally be controlled by JNK1 or JNK2. Differences in the gene expression profiles between Jnk1-/- and Jnk2-/- cells may explain the opposite roles JNK1 and JNK2 appear to play in TPA-promoted skin carcinogenesis (6 , 7) .

TPA Treatment Results in Differential Gene Expression in WT, Jnk1-/-, and Jnk2-/- Cells.
In WT cells, the products of most genes that were highly expressed appear to be related to inhibition of cell growth and induction of differentiation or apoptosis (clusters 4 and 5 and partial cluster 6), which generally would suggest antitumorigenic roles. For example, CIP1/WAF1, cyclin-dependent kinase 4/6 inhibitor, and insulin-like growth factor-binding protein 6 in cluster 5 (10) have been found to inhibit cell growth and modulate the cell cycle. Elevated levels of JunD (cluster 6) have been found to lead to suppressed transformation induced by a ras gene (11) . The Bcl-2 antagonist (BAK) in cluster 4 (12) , the BAX membrane isoform (cluster 4; Ref. 13 ), and the lymphotoxin receptor (tumor necrosis factor receptor family; cluster 5; Ref. 14 ) have been found to mediate cellular apoptosis; and granzyme C (cluster 6) is an important cytotoxic proteinase similar to granzyme B. GST-{pi}1 (cluster 5; Ref. 15 ) and NM23 (cluster 4) inhibit tumorigenesis and metastases. Our results indicate that after TPA treatment of WT cells, the expression of the genes encoding these proteins was suppressed, suggesting that the inhibition of these genes may be related to a susceptibility to TPA-induced tumorigenesis.

Our in vivo studies indicated that Jnk1 knockout mice had an increased susceptibility to TPA-induced tumorigenesis. In Jnk1-deficient cells, most of the genes that are highly expressed (cluster 4) do not change after TPA treatment, indicating that these genes may not be important in TPA-induced tumorigenesis. On the other hand, in Jnk1-/- cells, TPA up-regulates 16 genes and down-regulates 7 genes in other clusters (clusters 1 and 5). The up-regulated genes include the genes encoding well-known antiapoptosis proteins, A20 zinc finger protein (TNFIP3; cluster 1; Ref. 16 ), GST5-5 (cluster 1; Ref. 17 ), and c-akt oncoprotein (cluster 5; Ref. 18 ). Compared with untreated WT cells, expression of these genes is either not changed (TNFIP3), decreased (c-akt), or slightly increased (GST5–5) in TPA-treated WT cells. The gene profile of expression of antiapoptosis genes induced by TPA in Jnk1-/- cells is thus increased compared with WT cells, which may help to explain why skin tumorigenesis is enhanced in Jnk1-/- mice compared with WT mice (7) .

Our studies have also indicated that TPA-induced tumorigenesis is suppressed in Jnk2-/- mice. In Jnk2-/- cells or TPA-treated Jnk2-/- cells, the profiles of gene expression are completely different from those of untreated or TPA-treated WT or Jnk1-/- cells. Most of the genes highly expressed in TPA-treated Jnk2-/- cells (clusters 5 and 6) are related to tumor suppression and induction of cell differentiation, apoptosis, or cell growth arrest. For example, JunB and JunD are markedly induced by TPA in Jnk2-/- cells, but JunB is unchanged, and JunD is markedly inhibited by TPA in both WT and Jnk1-/- cells. JunB and JunD proteins are components of the activator protein 1/jun family. However, recent studies have shown that JunB and JunD interfere with DNA binding activity and transcriptional activity of c-Jun and c-Fos, resulting in a decrease of c-Jun/c-Fos-induced activator protein 1 transcription activity (11) . Elevated levels of JunD have been found to lead to suppressed transformation induced by a ras gene (11 , 19) . JunB expression is required for neuronal differentiation, and JunB and c-Jun have opposite functions in regulation of cell growth (20) . Thus, up-regulation of JunB and JunD in Jnk2-/- cells exposed to TPA may result in an antitumorigenic effect. The genes encoding early growth response protein 1 and TPA-induced sequence 11 are two early expression genes induced by TPA. In this study, they both had only slightly increased expression in TPA-treated WT cells or TPA-treated Jnk1-/- cells but were strongly stimulated by TPA in Jnk2-/- cells (cluster 6 of Fig. 2Citation ). Early growth response protein 1 has been found to be related to TPA-induced differentiation of leukemia cells induced by TPA (21) , and TPA-induced sequence 11 was shown to be an inhibitor of stem cell proliferation. These results also may be significant in explaining why Jnk2-/- mice are more resistant to TPA-induced tumorigenesis. Another two genes highly expressed in TPA-treated Jnk2-/- cells are genes encoding T-cell death-associated protein (TDAG51) and granzyme C (cluster 6), which function to promote apoptosis. TDAG51 has been shown to be a strong proapoptosis protein that couples to Fas expression (22) , and granzyme C is an important cytotoxic proteinase similar to granzyme B. This suggests that TPA treatment increases the capability for apoptosis in Jnk2-/- cells, thus possibly enhancing protection against TPA-induced tumorigenesis.

Some significant genes that are highly expressed in Jnk2-/- cells are down-regulated after TPA treatment (clusters 1 and 2). For example, GST5-5 has an antioxidant function that is very important in protecting the cell membrane from free radical damage (17) , and A20 zinc finger protein (TNFIP3) is an inhibitor of apoptosis (16) . Both genes encoding GST5-5 and TNFIP3 expressed at high levels in untreated Jnk2-/- cells are down-regulated after TPA treatment, indicating that these cells may be more susceptible to death after TPA treatment. The gene encoding interleukin 11, which mainly stimulates cell proliferation, is also down-regulated in TPA-treated Jnk2-/- cells, indicating that cell proliferation may be inhibited after TPA treatment. Expression of several genes that encode proteins with important functions in determining susceptibility to tumorigenesis is altered in TPA-treated Jnk2-/- cells. These alterations generally would appear to explain our observation that Jnk2-deficient mice have an increased resistance to TPA-induced tumorigenesis (6) .

In summary, we found that the patterns of gene expression among untreated and TPA-treated Jnk1-/-, Jnk2-/-, and WT cells are different and suggest that both JNK1 and JNK2 proteins may have different roles in modulating cell function. After TPA treatment, the changes in the gene expression profiles of WT, Jnk1-/-, and Jnk2-/- cells provide insight into the differential responses of Jnk1-/- and Jnk2-/- mice to 7,12-dimethylbenz(a)anthracene/TPA-induced skin carcinogenesis.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by the Hormel Foundation and Eagles Cancer Telethon Foundation. Back

2 To whom requests for reprints should be addressed, at The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912. Phone: (507) 437-9600; Fax: (507) 437-9606; E-mail: zgdong{at}hi.umn.edu. Back

3 The abbreviations used are: JNK, c-Jun NH2-terminal kinase; FBS, fetal bovine serum; MAPK, mitogen-activated protein kinase; TPA, 12-O-tetradecanoylphorbol-13-acetate; RT-PCR, reverse transcription-PCR; WT, wild-type; GST, glutathione S-transferase. Back

4 http://rana.stanford.edu/software. Back

Received 11/ 2/01. Accepted 1/10/02.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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Z. Gao, A. Zuberi, M. J. Quon, Z. Dong, and J. Ye
Aspirin Inhibits Serine Phosphorylation of Insulin Receptor Substrate 1 in Tumor Necrosis Factor-treated Cells through Targeting Multiple Serine Kinases
J. Biol. Chem., June 27, 2003; 278(27): 24944 - 24950.
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