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1 Research Institute of Genetic Engineering, Pusan National University, Busan 609-735, Korea
2 Department of Molecular Biology, Pusan National University, Busan 609-735, Korea
3 Department of Applied Biology, Insect Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
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Introduction |
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The homodimeric transcription factor, DNA replication-related element (DRE)-binding factor (DREF), has been shown to perform a crucial role in the regulation of DNA replication- and cell proliferation-related genes via binding to the DRE site (5'-TATCGATA) of the target genes (Hirose et al. 1993; Ryu et al. 1997; Hyun et al. 2005). DREF also modulates the transcription of the Drosophila mitochondrial transcription factor A (D-mtTFA) gene (Takata et al. 2001), and the accessory subunit gene of Drosophila mitochondrial DNA polymerase (Lefai et al. 2000). The DNA binding activity of DREF is regulated directly by elevated levels of ROS (Choi et al. 2004), and this activity is modulated via the intracellular redox state (Park et al. 2004). It was reported that ectopic DREF expression in Drosophila eye and wing imaginal disc cells induces both apoptosis and aberrant morphogenesis (Hirose et al. 2001; Yoshida et al. 2001).
In the current study, we have identified three putative DRE sequences located within the 5'-flanking region of the dANT gene, and have evaluated the role of DREF in the transcriptional regulation of the dANT gene. Our results show that DREF binds to the three DRE sites in the dANT gene promoter, and performs a critical role in dANT promoter activity via the DRE sites.
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Results |
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We found three consensus DRE sequences, TATCGATA, located within the 5'-flanking region of the dANT gene, via a public database search (GENBANK accession no. AE003484) (Fig. 1). These sequences were designated dANT-DRE1, dANT-DRE2 and dANT-DRE3. In order to determine whether DREF is capable of recognizing the putative binding sites located within the dANT promoter region, gel mobility shift assays were conducted using Kc cell extracts, and three dANT-DRE wt oligonucleotides were labeled as probes. Binding complexes were detected, and efficiently competed for via the inclusions of unlabeled dANT-DRE1, dANT-DRE2, or dANT-DRE3 wt oligonucleotides, respectively, in the binding reaction (Fig. 2, lanes 2 and 3; lanes 7 and 8; lanes 12 and 13), but not by inclusions of dANT-DRE1mut, dANT-DRE2mut or dANT-DRE3mut oligonucleotides harboring base substitutions within the DRE sequence (Fig. 2, lanes 4, 9 and 14). The addition of an anti-DREF monoclonal antibody (mAb 4) to the binding reaction resulted in a supershift of the protein-DNA complexes (Fig. 2, lanes 5, 10 and 15). These results showed some differences in binding affinity among the three elements. DRE3 was the most evidently competed by the unlabeled competitor while DRE2 was modestly and DRE1 was hardly competitive for the unlabeled fragments, respectively. These findings show that DREF binds to all three dANT-DRE sites within the 5'-flanking region of the dANT gene in a sequence-specific manner.
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As DREF binds to three potential DRE sequences within the 5'-flanking region of the dANT gene, we analyzed the significance of the DRE sites for the expression of dANT. In order to determine the role of the DRE sites in dANT promoter activity, we constructed reporter plasmids harboring the dANT promoter region (–1075 to +60 with respect to the transcription initiation site) with or without mutations in the DREs that had been fused to a luciferase reporter (Fig. 3). The plasmids were then transfected into Drosophila Kc cells and the levels of luciferase expression were determined. As is shown in Fig. 3, the luciferase activities of a single mutation in the dANT-DRE1, dANT-DRE2 or dANT-DRE3 sites were determined to be only slightly less than those of the wild-type. Also, expression levels of the dANT-DREmut1, 2-luciferase and dANT-DREmut1,3-luciferase fusion genes were unchanged, but mutations in dANT-DRE2,3 and dANT-DRE1,2,3 resulted in the extensive reduction of luciferase expression. Therefore, the results that the combinational mutation of DRE2 and DRE3 evidenced more profound effects than were observed with the other double mutations suggested different affinities and significances of the three elements.
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We then attempted to determine whether DREF regulates dANT gene expression via the GAL4-UAS system. To investigate whether the reduction of endogenous DREF reduces the level of dANT mRNA, we conducted RT-PCR analysis of UAS-dref-IR/+; Da-GAL4/+ embryos. When the expression of DREF mRNA was reduced in the UAS-dref-IR/+; Da-GAL4/+, the level of sesB mRNA was lower than that in the embryo harboring a single copy of Da-GAL4 (Fig. 5A). We also detected the reduction of sesB mRNA levels in the DREFKG09294 mutant flies (Fig. 5B). As it was recently reported that the adult Drosophila midgut undergoes rapid cell turnover, similarly to the vertebrate intestine, and the fundamental similarities between Drosophila and vertebrate intestines and their stem cells were assessed (Micchelli & Perrimon 2006; Ohlstein & Spradling 2006), the effect of the reduction of endogenous DREF on the ANT promoter activity of the adult gut was determined. Transgenic flies harboring UAS-dref-IR were crossed with transgenic flies harboring GAL4 cDNA under the control of the Hsp70 gene promoter (hs-GAL4). The expression level of ß-galactosidase activity in the heat-shocked adult posterior midgut and hindgut of hs-GAL4/+; UAS-dref-IR/+; dANT-lacZ/+ was generally lower than in the line harboring hs-GAL4/+;+/+; dANT-lacZ/+ (Fig. 5C). To confirm the down-regulation of dANT expression by dref-IR, quantitative analysis of ß-galactosidase activity in the adult gut was conducted. The level of ß-galactosidase activity in the heat-shocked UAS-dref-IR/+; dANT-lacZ/+; hs-GAL4/+ was 0.68-fold lower than that of the heat-shocked+/+; dANT-lacZ/+; hs-GAL4/+ (Fig. 5D). These results indicate that DREF is a prerequisite for dANT promoter activity within the adult gut. We assessed the expression of dANT-lacZ in the eye imaginal discs in which DREF was over-expressed under the GMR-GAL4 driver. The level of ß-galactosidase activity in the eye imaginal disc of GMR-GAL4/+; UAS-DREF/+; dANT-lacZ/+ larvae was higher than that of the larvae harboring GMR-GAL4/+;+/+; dANT-lacZ/+ (Fig. 5E). The up-regulation of dANT expression by DREF was also verified via RT-PCR (Fig. 5F). Increased DREF mRNA was detected in the eye imaginal discs of third larvae harboring single copies of both GMR-GAL4 and UAS-DREF. The level of sesB mRNA in GMR-GAL4/+; UAS-DREF/+ was higher than that in the larvae harboring a single copy of GMR-GAL4. These results show that DREF is a key regulator for dANT promoter activity both throughout development and in adulthood.
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DREF over-expression in the region posterior to the MF of eye imaginal disc cells has been reported to induce a rough eye phenotype and induce apoptosis (Hirose et al. 2001). In mammals, the expression of ANT1 has been reported to induce apoptosis and the collapse of mitochondrial membrane potential (Bauer et al. 1999), and the expression of the ANT2 gene is involved in the regulation of glycolytic ATP importation into the mitochondria, which is required for the maintenance of the mitochondrial membrane potential (Buchet & Godinot 1998). In order to determine whether DREF-induced phenotypes are associated with the up-regulation of dANT by DREF, membrane potential was measured using JC-1 dye in the eye imaginal discs of third larvae in which DREF was over-expressed. The dye enters living cells and fluoresces bright red in its multimeric form within active mitochondria. In apoptotic cells, the mitochondrial membrane potential collapses, and the JC-1 dye does not manifest its multimeric form within the mitochondria, thus remaining in the cytoplasm in its green J-monomeric form (Kuhnel et al. 1997). We verified that DREF over-expression under the GMR-GAL4 driver induces apoptosis in eye imaginal disc cells (Fig. 6B). When the eye imaginal discs of the control GMR-GAL4/+;+/+ were stained with JC-1 and visualized under fluorescent microscopy, they evidenced orange mitochondrial staining (Fig. 6C). However, GMR-GAL4/+; UAS-DREF/+ manifested only green fluorescence, or markedly reduced orange mitochondrial staining within the posterior regions of the eye imaginal disc cells (Fig. 6D). The eye imaginal discs of the GMR-GAL4/+; UAS-sesB/+ were also showed apoptosis and reduced orange mitochondrial staining (Fig. 6E and F). This indicates that mitochondrial membrane potential is reduced in the eye imaginal discs in which DREF was over-expressed, thereby implying mitochondrial dysfunction as the result of the DREF-mediated up-regulation of Drosophila ANT.
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Discussion |
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Drosophila ANT genes are duplicated in a tandem fashion: sesB and ANT2. These two genes are transcribed from a common promoter, and their mRNAs are generated via differential splicing (Zhang et al. 1999). In the present study, although the expression of dANT-lacZ harboring a dANT gene (–1075 to +60 with respect to the transcription initiation site) fused to the lacZ reporter evidences a ubiquitous signal throughout the developmental stages, the expression of dANT-lacZ was detected abundantly in the imaginal discs and guts of third larvae (Fig. 4A) and the guts and reproductive systems of transgenic adults (Fig. 4B). To know whether the promoter fragment (–1075 ~ +60 bp) can recapitulate the expression pattern of the endogenous dANT gene, in situ hybridization or immunostaining using dANT antibody would be required. The expression of dANT-DREmut-lacZ in the same tissues shows that DRE is required for the activity of the dANT promoter in these tissues. It was recently reported that the adult Drosophila midgut undergoes rapid cell turnover, similarly to the vertebrate intestine, and the fundamental similarities between Drosophila and vertebrate intestines have been revealed (Micchelli & Perrimon 2006; Ohlstein & Sparding 2006). The reproductive system is characterized by a high cellular proliferation rate (Narbonne et al. 2004). Therefore, the need for DRE in dANT promoter activity in the gut as well as in reproductive systems may be associated with the cell-proliferation of these tissues. In mammals, three different functional ANT genes encoding for proteins have been identified, and each of the ANT isoforms exhibits a tissue-specific expression pattern (Stepien et al. 1992). ANT1 is predominantly expressed in post-mitotic cell types in the skeletal muscles, the heart and the brain; ANT2 is expressed principally in highly proliferative tissue types (Giraud et al. 1998); and ANT3 is expressed ubiquitously (Stepien et al. 1992; Doerner et al. 1997). It has been reported that the expression of ANT isoforms is altered in a specific manner in both dilated cardiomyopathy and cancer cell glycolysis (Sylven et al. 1993; Chevrollier et al. 2005).
A human homologue of Drosophila DREF (hDREF/KIAA0785) has been identified (Ohshima et al. 2003). It was reported that the binding sequence with the highest affinity to the hDREF protein was 5'-TGTCG(C/T)GA(C/T)A. In particular, the 6-bp sequences within the center (5'-TCG(C/T)GA) are relevant to hDREF/KIAA0785 binding (Ohshima et al. 2003). Interestingly, we determined that the human ANT1 gene (Cozens et al. 1989; Li et al. 1989) harbors the hDREF binding sequence, TCGCGA, at the nucleotide position –45 to –40, with regard to the transcription initiation site, which concurs with the core 6-bp sequences in the center, and the human ANT2 gene (Ku et al. 1990) harbors two hDREF-like sequences at –55 to –46 and –519 to –510 with regard to the transcription initiation site. The human ANT3 gene (Cozens et al. 1989) also harbors the hDREF binding sequence, TCGCGA, which is concurrent with the core 6-bp sequences. These findings indicate that the regulation of the ANT gene in the DRE/DREF system might be conserved from Drosophila to mammals.
Furthermore, we detected strong dANT-lacZ expression and a remarkable reduction of dANT promoter activity as the result of DRE mutations in the larval and adult fat bodies, the fly equivalents of the mammalian liver and the white adipose tissues. Energy metabolism is closely associated with liver function, and mitochondria constitute the "energy factories" of cells. Adipose tissue has been consistently identified as relevant to the mediation of life-span via alterations in insulin/insulin-like growth factor signaling (Giannakou et al. 2004). The functions of the Drosophila fat body include many of the metabolic activities of the mammalian liver, as well as fat storage. We also previously assessed the expression of DREF in the Drosophila fat body via immunohistochemical analysis using DREF monoclonal antibody (Park et al. 2006). These results indicate the important role of DREF in the fat bodies.
In mammals, the expression of ANT isoforms in cancer cells is closely associated with the metabolic properties, cell cycle events, and maintenance of mitochondrial membrane potential (Chevrollier et al. 2005). In the current study, we determined that the eye imaginal disc cells of larvae in which DREF is over-expressed also displayed a loss or collapse of mitochondrial membrane potential. Mitochondrial membrane potential is essential to the maintenance of mitochondrial functions (Xu et al. 2001a), and can be compromised as the result of the opening of permeability transition pores at early stages of apoptosis (Xu et al. 2001b). The ectopic expression of UAS-DREF by the GMR-GAL4 driver resulted in a severe rough eye phenotype and also induced apoptosis in eye imaginal disc cells (Hirose et al. 2001). These facts suggest that DREF may perform a crucial role in mitochondrial function.
Collectively, these findings indicate that Drosophila ANT is a novel target gene of DRE/DREF, a key regulatory system of the cell proliferation-related gene.
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Experimental procedures |
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All oligonucleotides were chemically synthesized. Sequences containing the DRE sequences or base substitutions in the dANT promoter region was as follows: dANT-DRE1 wild-type (wt), 5'-GATCCTTAAAAAATATCGATATTGATGCTA-3 and 3'-GAATTTTTTATAGCTATAACTACGATCTAG-5'; dANT-DRE1 mutant (mut), 5'-GATCCTTAAAAAATTAGGATATTGATGCTA-3 and 3'-GAATTTTTTAATCCTATAACTACGATCTAG-5'; dANT-DRE2 wt, 5'-GATCCTAGCTGAATATCGATAGATCGCCGA-3' and 3'-GATCGACTTATAGCTATCTAGCGGCTCTAG-5'; dANT-DRE2 mut, 5'-GATCCTAGCTGAATTAGGATAGATCGCCGA-3' and 3'-GATCGACTTAATCCTATCTAGCGGCTCTAG-5'; dANT-DRE3 wt, 5'-GATCCAAAGCAACTATCGATATGCGGTATA-3' and 3'-GTTTCGTTGATAGCTATACGCCATATCTAG-5'; dANT-DRE3 mut, 5'-GATCC-AAAGCAACTTAGGATATGCGGTATA-3' and 3'-GTTTCGTTGAATCCTATACGCCATATCTAG-5'. Double-stranded oligonucleotides for site-directed mutagenesis were as follows: dANT-DRE1mut, 5'-AAAAATTAGGATATTGATGCTTCAATCCCC-3' and 3'-TTTTTAATCCTATAACTACGAAGTTAGGGG-5'; dANT-DRE2 mut, 5'-ATCTAGCTGAATTAGGATAGATCGCCGAAT-3' and 3'-TAGATCGACTTAATCCTATCTAGCGGCTTA-5'; dANT-DRE3 mut, 5'-CCAGTTAAAGCAACTTAGGATATGCGGTAT-3' and 3'-GGTCAATTTCGTTGAATCCTATACGCCATA-5'. Mutated bases are underlined, and the used primers contained BglII and BamHI linker.
Oligonucleotides for the RT-PCR of sesB were as follow: sesB, 5'-GCGGCGGCCGCATGGGCAAGGATTTCGAT-3' and 3'-AGAATGGTGCTTGTTGCCGAGCTCGCG-5'. The used primers contained 5'-NotI and 3'-XhoI linker. Specific primers for RT-PCR of DREF and rp49 were previously described (Park et al. 2004).
Plasmid constructions
The promoter region of the dANT gene (–1075 to +60 with respect to the transcription initiation site) was cloned by polymerase chain reaction (PCR) using Drosophila genomic DNA. Sequence analysis was performed to confirm the nucleotide sequence. The primers used, containing the linker sequences BamHI were as follows: 5'-GCGGGATCCCTAAATTGTATCCCAAGG-3' and 3'-GACTAAGACGTTTTCTTC-CCTAGGGCG-5'. Amplified 1104 bp fragments were subcloned into the BamHI site of the pBluescript II KS (+/–) (Stratagene) vector and then into 5'-SmaI and 3'-SacI sites of the pGL2-Basic (Promega). To construct the plasmid dANT-lacZ for transgenic flies, the dANT promoter region was inserted into the BamHI site of the plasmid pCaSpeR-AUG-ß-gal.
Site-directed mutagenesis
To obtain the pdANT-DREmut-Luc mutant reporter plasmids carrying base substitution mutations in the DRE in the 5'-fanking region of the dANT gene, the mutagenesis reaction was carried out on double-stranded DNA of pdANT-Luc using the QuickChangeTM Site-Directed Mutagenesis Kit (Stratagene). The reaction was set up essentially as recommended by the manufacturer. The mutation and the fidelity of the remaining DNA were confirmed by sequencing.
Cell culture and DNA transfection
Drosophila Kc cells were grown at 25 °C in M3 (BF) medium (Sigma) supplemented with 2% fetal bovine serum (FBS) and 0.5% penicillin/streptomycin (Gibco BRL), respectively. Transfection of various DNA mixtures into Kc cells was performed using dimethyldioctadecyl ammonium bromide (DDAB) and the cells were harvested 48 h thereafter. The luciferase assay was carried out by means of a Luciferase Assay System (Promega), as previously described (Choi et al. 2004). Luciferase activity was normalized with ß-galactosidase activity to correct for transfection efficiency.
Preparation of nuclear extracts
Preparation of nuclear extracts from Drosophila Kc cells was performed as previously described (Hirose et al. 1993) with modifications. Briefly, cells were rinsed once using ice-cold phosphatebuffered saline (PBS). Cells were collected by centrifugation at 1550 g for 5 min, resuspended in buffer A (10 mM HEPES, 1.5 mM MgCl2, 10 mM NaCl and 0.25% NP-40, pH 7.5) and incubated on ice for 5 min, followed by centrifugation at 4000 r.p.m. for 5 min. The supernatant (cytosolic extracts) was removed and the nuclei were extracted with buffer C (20 mM HEPES, 25% glycerol, 1.5 mM MgCl2, 420 mM NaCl, 0.2 mM EDTA and 0.25% NP-40, pH 7.5). The nuclei were vortexed vigorously several times for 20 min, followed by centrifugation at 14 000 r.p.m. for 5 min. The supernatant (nuclear extract) was transferred into fresh tubes and diluted 1 : 2 with buffer D (20 mM HEPES, 50 mM KCl, 0.2 mM EDTA and 20% glycerol, pH 7.5) and frozen at 80 °C until use.
Electrophoretic gel-mobility shift assay (EMSA)
EMSA was performed as previously described (Choi et al. 2000). Kc cell nuclear extracts were incubated in 10–20 mL of reaction mixture containing 10 mM HEPES (pH 7.6), 50 mM KCl, 1 mM EDTA, 5% glycerol and 0.5 mg of poly (dI–dC) for 10–20 min at room temperature. Unlabeled competitor oligonucleotides were also added at this step. Each of the 32P-labeled oligonucleotides (1 x 105 c.p.m) was added and the mixture was incubated further for 20 min at room temperature. In the case of gel-shift assay performed with anti-DREF monoclonal antibody (mAb 4) (Hirose et al. 2001), Kc cell nuclear extract was incubated in a reaction mixture described above with mAb 4 for 20 min before the addition of radiolabeled oligonucleotides. The retarded bands were resolved electrophoretically on a 4%–6% non-denaturing Tris-borate-EDTA polyacrylamide gel. The gels were dried and autoradiographed with X-ray film or analyzed with a BAS 2000 imaging analyzer.
Fly stocks and establishment of transgenic flies
Fly stocks were maintained at 25 °C on standard food. To establish transgenic flies carrying pdANT-lacZ or pdANT-DREmut-lacZ, P-element mediated germ line transformation was carried out essentially as previously described (Sparding 1986). Three independent lines were obtained with pdANT-lacZ and pdANT-DREmut-lacZ constructs, respectively. The line carrying the same fusion genes showed same lacZ expression patterns. The UAS-dref-IR strain was used for knockdown of DREF. For ectopic expression or knockdown of DREF using the GAL4-UAS system, Da-GAL4, Hsp70-GAL4 (hs-GAL4), GMR-GAL4 (Takahashi et al. 1999) lines, the transgenic flies carrying UAS-DREF on the second chromosome (Hirose et al. 2001) and UAS-dref-IR strain (Yoshida et al. 2004) previously described were used. The DREFKG09294/CyO strain was kindly supplied by the Bloomington Stock Center. Oregon-R was used as the wild-type.
X-gal staining
The tissues were dissected and fixed for 15 min in PBS containing 0.5% glutaraldehyde, washed in PBS, and immersed in 0.2% X-gal (5-bromo-4-chloro-3-indolyl-ß-D-galactopyranocyde) in staining buffer containing 6.1 mM K4Fe(CN)6, 6.1 mM K3Fe(CN)6, 1 mM MgCl2, 150 mM NaCl, 10 mM Na2HPO4 and 10 mM NaH2PO4). Incubation was in the dark at 37 °C.
Quantitative measurement of ß-galactosidase activity in extracts
Quantitative measurement of ß-galactosidase activity in extracts prepared from Drosophila guts were conducted as previously described (Ha & Yoo 1997). ß-Galactosidase activity was defined as absorbance units/mg of protein/h.
RT-PCR
Total RNA from larvae was isolated with Trizol reagent (Molecular Research Center, Inc.) according to the protocol furnished by the manufacturer. cDNAs were synthesized with M-MLV-RT (Promega). The RT-PCR products were analyzed on 1.5% agarose gels stained with ethidium bromide.
Acridine orange staining
Acridine orange staining was conducted according to Abrams et al. (1993) with minor modifications. Dissected eye imaginal discs were incubated for 10 min in PBS containing 5 µg/mL of acridine orange. The organs were placed in fresh PBS and analyzed immediately for nuclear staining on Zeiss Axioskop Fluorescence microscope. Elapsed time from dissection of the tissue was restricted to 20 min.
Staining with mitochondria-specific fluorescence
The changes in mitochondrial membrane potential were monitored with the dye 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide (JC-1; Molecular Probes, Eugene, OR, USA) (Reer et al. 1991). Dissected eye imaginal discs were stained with JC-1 (10 µg/mL) at 25 °C for 15 min and rinsed 3 times with PBS. The observation was made by using a fluorescent microscope. JC-1 is a radiometric, dual-emission fluorescent dye and localizes within the mitochondria in proportion to mitochondrial membrane potential and forms aggregates that fluoresces red (excitation 550 nm; emission 600 nm). When mitochondrial membrane potential dissipates, JC-1 dye leaks into the cytoplasm and fluorescence green (excitation 485 nm; emission 535 nm).
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Acknowledgements |
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Footnotes |
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* Correspondence: E-mail: mayoo{at}pusan.ac.kr
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References |
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Received: 9 October 2006
Accepted: 29 January 2007
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