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1 Divisions of Oncology
2 Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
3 Department of Life Science and Human Technology, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan
4 Depertment of Molecular Medicine, Faculty of Medicine, Osaka University, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
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Abstract |
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 Top Abstract IntroductionResultsDiscussionExperimental proceduresReferences |
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Introduction |
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TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
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Accumulating evidence shows that Tob family proteins interact with transcription machineries. For example, the Tob family proteins interact with Caf1, CCR (carbon catabolite repression) 4-associated factor 1 (Rouault et al. 1998; Ikematsu et al. 1999), that is involved in transcription of a number of genes including a gene coding for alcohol dehydrogenase II in yeast (Denis 1984). Btg1 and Btg2/Tis21/PC3 interact with protein-arginine N-methyltransferase 1 (PRMT1), Hoxb9, and estrogen receptor 
(Lin et al. 1996; Prevot et al. 2000, 2001). Tob interacts with Smads to regulate an osteoblast differentiation and proliferation and T cell response (Yoshida et al. 2000; Tzachanis et al. 2001). Thus, Tob family proteins are implicated in transcriptional regulation. Quite intriguingly, recent evidence shows that Caf1 and CCR4 are associated with deadenylase activity (Tucker et al. 2001), which raises a possibility that Tob family proteins may as well be involved in mRNA regulation.
Recent report showed that tob mRNA was highly expressed in anergic T cells and Tob was involved in regulation of interleukin-2 (IL-2) transcription through an enhancement of Smad binding on negative regulatory element of IL-2 promoter (Tzachanis et al. 2001). Stimulation of the T cell receptor (TCR) without CD28 induces T cell anergy that is characterized by inability to produce IL-2 (reviewed in Schwartz 1997). In anergic fresh T cells, no IL-2 was produced, whereas synthesis of IL-2 mRNA was reduced only half. Although IL-2 mRNA was destabilized upon anergic stimulation (Lindstein et al. 1989), mature IL-2 mRNA still remained in anergic T cells. The data implicates a possible translational regulation of IL-2 in addition to transcriptional regulation. Interestingly, IL-2 mRNA was not distributed within polyribosome fractions when freshly isolated human T cells were anergized (Garcia-Sanz & Lenig 1996). However, molecular mechanisms of the translational blockade of IL-2 mRNA in T cell anergy remain to be elucidated.
Regulation of translation and transcription is important for the control of cell growth and differentiation. Translation initiation is well regulated by initiation factors, such as eIF4E and eIF4G as well as poly(A)-binding protein PABP (reviewed in Gallie 1998; Mathews et al. 2000). Importantly, initiation factor complex containing eIF4G interacts with PABP either directly or indirectly and through this interaction 5' end of mRNA meets to its own 3' end, resulting in circularization of mRNA. The circularized mRNA promotes the 60S ribosomal-joining to form the 80S ribosomal initiation complex (reviewed in Jacobson 1996). PABP was originally identified in a nucleoprotein complex (Blobel 1973) and contains conserved four RNA-recognition motifs (RRM) in the amino-terminal region. RRM1 and RRM2 are responsible for binding of PABP to the 3' poly(A) sequence of mRNA (reviewed in Burd & Dreyfuss 1994). The carboxyl-terminal region of PABP (termed PABC domain) interacts with various proteins, such as Paip1 (Craig et al. 1998; Gray et al. 2000), Paip2 (Khaleghpour et al. 2001) and eukaryotic releasing factor 3 (eRF3) (Hoshino et al. 1999), and thus is thought to be important for regulation of mRNA translation. Inducible PABP (iPABP) is a homolog of PABP, identified in differential screening of activated human CD28(+) T cells (Yang et al. 1995). Expression of iPABP is indeed induced upon stimulation of peripheral T cells. RRMs of PABP and iPABP are almost identical, but their carboxyl-terminal halves, except for the PABC domains, are divergent having only 45% identical amino acids.
In the present report we show that Tob interacts with iPABP as well as PABP. We provide evidence suggesting that Tob negatively regulates iPABP-mediated enhancement of translation of IL-2 mRNA.
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Results |
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To identify proteins that interacted with Tob, we performed far-Western screening of a Jurkat leukemia cDNA library using the amino-terminal half of Tob as a probe. We isolated four positive clones as Tob-interacting proteins. Nucleotide sequencing revealed that clone 1 encoded full-length poly(A)-binding protein (PABP), and that the other three encoded various lengths of inducible poly(A)-binding protein (iPABP): clone 2 and clone 3 encoded full-length iPABP, and clone 4 encoded iPABP lacking the amino-terminal RRM1 and a part of RRM2 (Fig. 1A).
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Because amino-terminal half of Tob (amino acid residues 1–170) was used as a probe in the initial screening, the sequence of 170 amino acids was sufficient for its interaction with PABP and iPABP. To further confine the interaction site on Tob, we constructed Flag-Tob expression plasmids pME-F-TobN113 containing amino-terminal 113 amino acids and pME-F-TobC114 containing the rest of carboxyl-terminal sequence (residues 114–363). After transfection of the plasmids together with pME-Myc-iPABP into HEK293 cells, the cell lysates were analyzed by co-immunoprecipitation and blotting. As shown in Fig. 1C, iPABP interacted with Tob at the carboxyl-terminal sequence. Taken together, we concluded that the region between amino acid residue 114 and 170 in Tob was sufficient for its interaction with iPABP.
To define the interaction site on iPABP and PABP, the Flag-tagged Tob construct was transfected into HEK293T cells together with the expression plasmid for Myc-tagged PABP, iPABP or one of the Myc-tagged iPABP deletion mutants (Fig. 1D, top). Anti-Flag immunoprecipitates from the lysates of the transfectants were probed with anti-Myc antibody by Western blotting. As shown in Fig. 1D, both Myc-PABP and Myc-iPABP bound to Flag-Tob (lanes 1–4). The results further showed that the carboxyl-terminus proximal sequence (amino acid residues 581–605) was required for the interaction (Fig. 1D, lanes 4–8). Consistently, GST-iPABP(C) containing carboxyl-terminal 127 amino acids of iPABP, but not GST-iPABP(RRM1) containing its amino-terminal 89 amino acids, interacted with Flag-Tob (Fig. 1B, lanes 4 and 5).
Translation of IL-2 mRNA is enhanced by iPABP and inhibited by Tob
As PABP is involved in translational control, iPABP could also regulate translation. iPABP was induced along with T cell activation that was associated with IL-2 expression. Therefore, we addressed whether iPABP was relevant to IL-2 expression and whether the interaction between iPABP and Tob affected IL-2 expression. First we synthesized mRNA in vitro from IL-2 cDNA that contained the sequences for 5' untranslated region (UTR) and 3'UTR and poly(dA). We also prepared luciferase mRNA containing poly(A) by in vitro transcription. Then the mRNAs were preincubated with purified iPABP and then subjected to an in vitro translation with or without Tob. As shown in Fig. 2A, iPABP enhanced translation of IL-2 mRNA but not that of luciferase mRNA.
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that carried deletion from residues 581–645 of iPABP and analyzed its effect on translation as above. Myc-iPABP did not coimunoprecipitated with Flag-Tob (Fig. 1D). As shown in Fig. 2A (lanes 10 and 11), Myc-iPABP also enhanced, albeit a little less effectively, IL-2 translation in vitro. This enhancement was not inhibited by the presence of Tob, suggesting that Tob mediated its inhibitory effect through its interaction with iPABP. Next, we examined a possible involvement of 3'UTR of IL-2 mRNA in iPABP-mediated enhancement of translation, because 3'UTR of mRNA was also involved in a formation of mRNP with PABP (Mohr et al. 2001). Translation from IL-2 mRNA (3'UTR– polyA–) that lacks both 3'UTR and poly(A) stretch was less than that from IL-2 mRNA (Fig. 2C, lane 1 and 10). Both PABP and iPABP did not enhance translation of IL-2 mRNA (3'UTR– polyA–) (Fig. 2C, lane 11 and 12). Furthermore, to address the significance of 3'UTR, we prepared IL-2 mRNA species lacking either 3'UTR or poly(A) or both, and compared their abilities to respond to iPABP and PABP with that of IL-2 mRNA containing both 3'UTR and poly(A). The results showed that 3'UTR was required for the enhancement of translation of IL-2 mRNA (Fig. 2C, lanes 2, 5, 8, and 11) and both 3'UTR and poly(A) stretch was required for the specific inhibition of IL-2 mRNA translation by Tob (lanes 3, 6, 9 and 12).
Involvement of iPABP-Tob in translation of IL-2 mRNA in mammalian cells
Next, we examined the effect of iPABP and Tob on translation of IL-2 mRNA in vivo. Because both transcriptional activity of IL-2 gene and stability of IL-2 mRNA change upon T cell stimulation, it is difficult to evaluate the translational contribution to IL2 expression in vivo. Then, we contrived an in vivo experimental system in which IL-2 mRNA was constantly supplied without endogenous transcriptional regulation. At first, we prepared NIH3T3 cells in which Myc-iPABP was stably expressed (NIH-iPABP). Then, IL-2 and GST expression vectors (pME-hIL-2 and pME-GST) were transfected together with or without Tob expression plasmid (pME-Flag-Tob) into the NIH-iPABP cells. Proteins in the lysates from the transfectants were subjected to Western blotting. As shown in Fig. 3, the production of IL-2 from the exogenous IL-2 cDNA in NIH-iPABP cells was enhanced as compared to parental NIH3T3 cells (upper panel, lanes 0 and 2). The enhancement of IL-2 production by iPABP was suppressed when Flag-Tob was over-expressed (Fig. 3A, upper panel). In contrast, Tob did not affect GST production. Tob does not suppress an enforced transcription of IL-2 gene driven by SR promoter (data not shown), in contrast to the inhibitory effect on endogenous IL-2 transcription in T cells (Tzachanis et al. 2001). Indeed, Northern analysis revealed that the levels of IL-2 and GST mRNAs were not affected by Tob expression (Fig. 3A: lower panel). These results indicated that the suppression of IL-2 protein production by Tob was not due to remarkable change of the amount of IL-2 mRNA, suggesting post-transcriptional regulation of IL-2 production by Tob.
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Finally, to investigate the biological significance of Tob–iPABP interaction, we isolated fresh human peripheral T cells. We first examined the levels of endogenous protein expression in anergic stimulated or activated T cells. Expression of IL-2, Tob, iPABP, and eIF4E were analyzed by immunoblotting. Upon TCR stimulation only with plate-bound anti-CD3 mAb, Tob was markedly induced, showing a peak protein level 6 h after the stimulation. Under this condition, expression of IL-2 mRNA was reduced and IL-2 protein was not produced (Fig. 4A). iPABP expression was weak and constant upon anergic stimulation (Fig. 4A). In contrast, stimulation of TCR with both plate-bound anti-CD3 mAb and CD28 resulted in induction of iPABP, IL-2 mRNA, and IL-2 protein, while Tob expression was not induced (Fig. 4A). The expression level of a main translation component, eIF4E was not changed upon anergic stimulation, even though it was enhanced during activation as reported (Mao et al. 1992). We examined the interaction between Tob and iPABP in both anergic and activated T cells. Lysates prepared from T cells stimulated for 6 h with anti-CD3 in the presence or absence of CD28 were immunoprecipitated with anti-Tob mAb and then probed with anti-iPABP pAb. Even though the basal expression level of iPABP protein was not high in anergic T cells, endogenous iPABP was co-immunoprecipitated with Tob in anergic T cells but not in activated T cells (Fig. 4B).
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Discussion |
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We identified iPABP and PABP as Tob-interacting proteins using the amino-terminal 170 amino acid sequence of Tob. We also showed that amino-terminal 113 amino acid residues of Tob were dispensable for the interaction. Therefore, a sequence between the residue 114 and 170 of Tob plays a part for its interaction with iPABP and PABP. The PABP-interacting molecules, such as Paip1, contain a consensus motif PAM2 that is an important binding site for the PABC domain (Roy et al. 2002). Tob contains two PAM2 motifs, one of which is located at the sequence between the residue 114 and 170 of Tob (Albrecht & Lengauer 2004). It is tempting to speculate that Tob prevents PABP–Paip1 interaction, because Tob shares the PABP binding sites with Paip1. Our experimental data suggested that the N-terminal PAM2 motif of Tob binds to the PABC domain. The importance of the C-terminal PAM2 motif on Tob–iPABP interaction remains to be investigated.
iPABP is up-regulated upon T cell activation (Yang et al. 1995), and thus could be involved in regulation of cytokine mRNAs that are also induced upon T cell activation. We have provided here evidence that iPABP stimulates translation of IL-2 mRNA. The effect of iPABP requires 3'UTR (Fig. 2C). PABP binds to 3'UTR as well as poly(A) tail and enhances the translation initiation of mRNA (Mohr et al. 2001). PABP could stabilize mRNA when it is tethered to 3'UTR of the target mRNA regardless of the presence or absence of poly(A) tail (Coller et al. 1998). Both PABP and iPABP bind AU-rich RNA sequences (AUR) and poly(A) with Kd in the same nM range (Sladic et al. 2004). 3'UTR of IL-2 mRNA possesses five AURs, which contribute to the translational activity of IL-2 mRNA (Lindstein et al. 1989). Consistently, we showed here that PABP and iPABP could enhance translation of IL-2 mRNA in a manner dependent to its 3'UTR (Fig. 2C). The enhancement of IL-2 mRNA translation by iPABP is prevented by the presence of Tob. The inhibition requires the interaction between Tob and iPABP, because Tob could not efficiently suppress IL-2 translation in the presence of iPABP that lacks the Tob interaction site (Fig. 2A). Importantly, inhibitory effect of Tob was not observed in an IL-2 mRNA lacking 3'UTR (Fig. 2C), either. Thus, Tob inhibits IL-2 mRNA translation by interacting with iPABP that recognizes 3'UTR. Since the level of IL-2 mRNA in NIH-iPABP cells is not reduced by Tob (Fig. 3), iPABP–Tob interaction is unlikely to induce marked instability of IL-2 mRNA. Loading of the 60S ribosome is facilitated by mRNA circularization (reviewed in Jacobson 1996; Chen & Sarnow 1995). In addition, we have preliminarily shown that Tob prevents IL-2 mRNA from accepting the 60S ribosome during translation initiation. Therefore, Tob is likely to interfere with the ability of iPABP to mediate circularization of IL-2 mRNA and formation of the translation initiation complex.
In T cells, IL-2 gene expression is regulated both at the transcriptional level and at the post-transcriptional levels, including control of stability (Lindstein et al. 1989), maturation and transport of mRNA (Gerez et al. 1995). There is a report that IL-2 mRNA is not distributed in polyribosome fractions in anergic T cells (Garcia-Sanz & Lenig 1996). Intriguingly, recent evidence shows that tob mRNA is highly expressed in anergic T cells. The report also shows that Tob negatively regulates transcription of IL-2 gene (Tzachanis et al. 2001). Taken together, suppression of IL-2 expression in anergic T cells takes place at transcriptional and translational levels, and Tob appears to be involved in both processes. In an in vitro translation system, the amount of template IL-2 mRNA added to the reaction mixture was abundant, and thus IL-2 mRNA translation may not be occurring efficiently. In naive T cells, the amount of IL-2 mRNA was reduced to half by inhibition of transcriptional activity of IL-2 gene, implicating that translational regulation of IL-2 mRNA by Tob could be more effective in vivo than expected from the in vitro experiments. Moreover, Tob is induced by anergic stimulation of T cells, which would also help prevent IL-2 production. Although expression of iPABP was induced upon T cell activation, the basal level of iPABP expression was detected in the other states. In addition, mature IL-2 mRNA was still present in anergic T cells. Therefore, it is possible that the basal level of iPABP promotes the translation of IL-2. Inhibition of IL-2 translation is important for anergic T cells, not in activated T cells. Thus, suppression of the IL-2 translation via the interaction between Tob and iPABP is important to strictly keep T cells at anergy or quiescent state. Tob may be important in T cells for inducing the rapid complete blockade of IL-2 production in the acute phase of anergic stimulation.
Although target-specificity of iPABP-Tob to IL-2 mRNA is still elusive, we suppose that the rigid discrimination of IL-2 mRNA by iPABP or PABP in T cells would be regulated by many cis/trans-acting factors recruited on to IL-2 mRNA. The selective entry of Tob-Smad complex into the transcription machinery of IL-2 gene (Tzachanis et al. 2001) might allow Tob for more efficient recognition of the IL-2 mRNP. Our data showed that over-expression of Tob resulted in suppression of IL-2 synthesis in cytoplasm and that iPABP was co-precipitated with Tob in cytoplasmic extract from T cells. We recently reported that Tob could shuttle between nucleus and cytoplasm, having functional nuclear localization signal and nuclear export signal (Tsuzuku et al. 2004). In addition, accumulating evidence implicates synchronized regulation of transcription and translation in gene expression. For example, regulation of processing and export of mRNA starts to take place within transcription machinery (Strasser et al. 2002). These may implicate that a specific recognition of target mRNA by Tob occurs at least in part during transcription.
In this paper, we provide significant evidence that translational regulation of IL-2 mRNA is mediated by the same nucleo-cytoplasmic protein Tob that also regulates transcription of IL-2 gene.
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Experimental procedures |
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The following monoclonal antibodies (mAbs) were purchased: anti-eIF4E mAb were from Transduction Laboratory, anti-human IL-2 mAb, anti-Myc mAb (9E10), anti-Flag mAb (M2), and anti-GST mAb from Santa Cruz. Azide free anti-human CD3 mAb (NU-T3) and anti-human CD28 mAb (KOLT-2) were kind gifts from Nichirei Corporation. Anti-Tob polyclonal antibody (pAb) was raised by an immunizing rabbit (New Zealand white) with the GST-TobN (amino acid 1–170) (Matsuda et al. 1996) and the anti-iPABP pAb was raised the same way as above with GST-iPABP(C) (amino acid 518–645).
Far-Western screening and nucleotide sequencing
Double-stranded and blunt-ended cDNAs were synthesized using mRNAs from Jurkat human leukemia T cells and random oligonucleotide primers. EcoRI and XhoI adapters were added to both ends, and the cDNA were inserted in the 
ZapII DNA. The cDNA library (about 5 x 105 independent plaques) was screened by the CORT method (Skolnik et al. 1991) using GST-TobN (amino acids 1–170) (Suzuki et al. 2001) as a probe. The probe protein was biotinylated and positive signals were detected with alkaline phosphatase-conjugated streptoavidins. Nucleotide sequences of the cloned DNAs were determined using an Auto-Read Sequencing Kit (Pharmacia Biotech).
Plasmid construction
For bacterial expression of proteins, the cDNAs encoding human Tob (amino acids 1–170), full-length human PABP, full-length human iPABP, iPABP(RRM1) (amino acids 1–89) and iPABP(C) (amino acids 518–645) were subcloned into pGEX-5X-1 vector (Pharmacia Biotec Inc.). To express proteins in mammalian cells, the Flag-tagged human Tob cDNA, Myc-tagged human PABP cDNA, Myc-tagged human iPABP cDNAs and human IL-2 cDNA (Yokota et al. 1987) were cloned in expression plasmid pME18S. GST mammalian expressing vector (GST-pME18S) was as described (Ishida et al. 1996). Each Myc-tagged deletion construct of iPABP was prepared by PCR amplification and ligation. The PCR-amplified sequence was confirmed by nucleotide sequencing.
In vitro pull-down and co-immunoprecipitation assay
HEK293T cells, NIH3T3 cells and their derivatives were grown in Dulbecco's Modified Eagle's Medium (DMEM) containing 10% FCS at 37 °C under 5% CO2. Cells were transfected with expression plasmids by lipofection methods as suggested by suppliers (Promega). The cells were lysed in TNE buffer containing 10 mM Tris-HCl (pH 7.8), 1% NP40, 0.15 M NaCl, 1 mM EDTA and 10 µg/mL aprotinin, and the lysates were centrifuged at 10 000 g for 40 min at 4 °C and the supernatants were used for experiments. For the pull-down assay, recombinant GST fusion proteins (100 µg) were incubated with glutathione-Sepharose beads (15 µg) by rotation at 4 °C for 1 h. After removal of the unbound fraction, the cell lysates were mixed with the beads in a TNE buffer by rotation for 30 min at 4 °C or subjected to co-immunoprecipitation assay.
In vitro translation products
Myc-tagged PABP, iPABP, iPABP (deleted a sequence from amino acid residues 579–637), and Flag-tagged Tob cDNA sequences were inserted into pBluescript downstream of T7 promoter. Each vector was subjected to an in vitro translation (Promega) and the products were labelled with 35S-methionine (Amersham). Translated products were collected with anti-Myc mAb or anti-Flag mAb, eluted, and concentrated in nuclease-free water. Protein products synthesized by in vitro translation were quantified using silver staining kit (Wako).
In vitro translation assay
The human IL-2 cDNA containing 3'UTR and poly(dA) stretch (Yokota et al. 1987) and luciferase cDNA with 3'UTR and poly(dA) stretch were inserted into pBluescript downstream of T7 promoter and linearized at the 3' end of the poly(dA) sequence. The IL-2 and luciferase mRNAs were produced by an in vitro transcription using Ribo Max Kit (Promega) and extracted by the acid-phenol method. The in vitro transcribed mRNAs (100 ng) were preincubated at 4 °C for 30 min with in vitro translated, 35S-labelled Myc-iPABP or Myc-iPABP (20–500 ng) and subjected to in vitro translation system (Promega) with 35S-methionine (Amersham) in the presence or the absence of in vitro translated, 35S-labelled Flag-Tob (4–500 ng). Initially, equal molar of transcribed mRNA and in vitro translated protein (Tob) were added to the reaction mixture, and subsequently dose dependent effect of Tob protein was analyzed. Total amounts of protein added were adjusted with nuclease-free BSA (Takara). Translated protein products were separated by 9–12.5% gradient SDS-PAGE. The gels were soaked in 2, 5-diphenyloxazole/DMSO (1/4) solution, and signals were detected by autoradiography.
Establishment of NIH3T3 cells over-expressing Myc-tagged-iPABP
NIH3T3 cells were co-transfected with pME18S-Myc-iPABP and pME18S-neo by the lipofection method (Tfx20; Promega). The transfected cells were grown in the same medium supplemented with G418 (400 µg/mL). The G418 resistant clones were screened by Western blotting for the expression of Myc-iPABP using the anti-Myc mAb. The NIH3T3 cells expressing Myc-tagged-iPABP (termed NIH-iPABP cells) were transfected with IL-2 and GST expression plasmids (pME-hIL-2 and pME-GST) together with two molar excess of pME-Flag-Tob or empty vector by lipofection.
Isolation of human peripheral T cells
Fresh human peripheral T cells were isolated by the negative selection method as following; Buffy coats were separated in a Ficoll-Hypaque (Pharmacia Biotech) density gradient centrifugation twice, after treatment with Erythrocyte Lysis Buffer (Quiagen). Dendritic cells were deleted by plastic absorption for 1.5 h at 37 °C, and macrophages were deleted by plastic absorption for 3.5 h at 37 °C twice in RPMI 1640 (JRH) supplemented with 10 mM HEPES (Gibco), 2 mM glutamine, 5 x 10–5 M 2-mercaptoethanol, 10 U/mL IL-2 (Pharmingen: PM19621T) and 5% FCS (Gibco). B cells were removed by nylon fibre (Wako) column separation, followed by panning on plates coated with 10 µg/mL anti-IgG (G18-145). Collected T cells were suspended in the same medium without IL-2 at 37 °C in a humidified incubator containing 5% CO2. T cells isolated by this procedure included both CD4+ and CD8+ T cells and more than 95% of the CD4+ T cells and 70% of the CD8+ T cells were CD28+.
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Acknowledgements |
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Footnotes |
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* Correspondence: E-mail: tyamamot{at}ims.u-tokyo.ac.jp
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Received: 11 August 2004
Accepted: 24 November 2004
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