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(Hypertension. 2001;37:419.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Nuclear Factor 1 Is a Negative Regulator of gadd153 Gene Expression in Vascular Smooth Muscle Cells

Michitsugu Nakamura; Takafumi Okura; Yutaka Kitami; Kunio Hiwada

From The Second Department of Internal Medicine, Ehime University School of Medicine, Ehime, Japan.

	Abstract

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Growth arrest and DNA damage inducible gene 153 (gadd153) is expressed at very low levels in growing cells but is markedly induced in response to cellular stresses, including glucose deprivation, exposure to genotoxic agents, and other growth-arresting situations. Forced expression of GADD153 can induce cell cycle arrest and/or apoptosis in many types of cells. Recently, we reported that GADD153 was induced in vascular smooth muscle cells (VSMCs) in neointimal lesions of balloon-injured carotid arteries. To investigate the underlying molecular mechanisms of gadd153 gene expression in VSMCs, we isolated and characterized a promoter region of the rat gadd153 gene. Sequence alignments of this region revealed 1 TATA-like sequence and several well-known cis elements. The 5'-deletion analysis for this region showed that a domain spanning -447 through -368 drastically reduced the promoter activity to almost equal levels of promoterless control. Because this domain contained a consensus sequence for the nuclear factor 1 family of proteins (NF1), DNA-binding studies were performed by use of 2 types of NF1 consensus probes. Both probes were specifically shifted by nuclear extracts from proliferating VSMCs and were supershifted by antiserum against CCAAT transcription factor/NF1. In addition, promoter activity of a mutant luciferase vector, which was generated by a point mutation at the NF1 binding motif of the gadd153 gene, was 14-fold higher than that of a wild-type one. These results suggest that gadd153 gene expression in VSMCs is negatively regulated by an NF1-binding motif, and NF1 may act as an antiapoptotic factor by continuously suppressing gadd153 gene expression in growing VSMCs.

Key Words: gadd153 • gene expression • apoptosis • carotid arteries • nuclear factor 1

	Introduction

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Growth arrest and DNA damage inducible gene 153 (gadd153) protein (GADD153) is a member of the CCAAT/enhancer-binding protein (C/EBP) family of transcriptional factors.¹ The expression levels of GADD153 are very low in normal growing cells but are highly induced in response to a variety of cellular stresses, including glucose deprivation, exposure to alkylating agents, and other growth-arresting situations.^{2 3 4} Microinjection of GADD153 into NIH-3T3 fibroblasts induces G₁ arrest,⁵ and the transient expression of GADD153 into different tumor cell lines also leads to growth arrest.⁶ Genes involved in cell differentiation and growth arrest are also potential candidates for apoptosis regulation.⁷

In atherosclerotic and restenotic lesions, the major cause of disease progression is believed to be excessive accumulation of cells.^{8 9} This accumulation is attributed to increased migration and/or proliferation of cells, including vascular smooth muscle cells (VSMCs), monocytes/macrophages, and T lymphocytes.^{10 11} Recent studies have demonstrated that dysregulated apoptosis plays an important role in the pathogenesis and progression of cardiovascular diseases.¹² These observations indicate that cell growth and apoptosis are 2 tightly linked processes in cardiovascular diseases, including atherosclerosis and restenosis. Recently, we have demonstrated that GADD153 plays an important role in VSMC apoptosis. In a balloon-injured carotid artery, GADD153 expression was highly induced in the apoptotic VSMCs that are often observed in neointimal lesions.¹³

In the present study, to investigate underlying molecular mechanisms of gadd153 gene expression in VSMCs, we isolated and characterized its 5'-flanking region, which contained a putative promoter of the gene, and showed that nuclear factor 1 (NF1) family proteins mainly repress a basal transcriptional activity of the gadd153 gene through binding to a negative regulatory element (NRE) seen in its promoter region.

	Methods

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Cloning of the Rat gadd153 Gene
A lambda DASH II rat genomic library originating from the testes of male Sprague-Dawley rats (Stratagene) was screened by a rat gadd153 cDNA as a probe.¹³ One genomic clone containing a 12-kbp sequence of the rat gadd153 gene was obtained, and a 1574-bp fragment that contained the nucleotide sequences spanning -1480 through +94 was excised by restriction enzyme digestion. This fragment was subcloned into the SacI/KpnI sites of the Bluescript II KS (+) vector (Stratagene). The resultant plasmid was designated as pKS-1,480, and an entire sequence of the inserted DNA fragment was determined on both strands.

Cell Culture
All surgical treatments conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985). VSMCs were isolated from 2 thoracic aortas of 10-week-old male Sprague-Dawley rats (Charles River Japan Inc, Kanagawa, Japan) as described previously.¹⁴ Cells (passages 3 to 10) were cultured in DMEM supplemented with 10% heat-inactivated FCS and were maintained at 37°C in a humidified atmosphere of 95% air/5% CO₂.

Plasmid Construction Used for Promoter Assay
Serial 5' deletions of the gadd153 gene promoter were prepared by standard methods by using a Kilo-Sequence Deletion Kit (Takara). Seven 5' deletions, which had the nucleotide sequences starting at the positions -1000, -447, -367, -273, -191, -100, and -50, were selected. Inserted DNA fragments were excised from pKS-1,480 and these 5' deletions, and they were ligated back into the promoterless firefly luciferase vector, pGL3-Basic (pGLB, Promega). Resultant plasmids were designated as Luc-1,480, Luc-1,000, Luc-447, Luc-367, Luc-273, Luc-191, Luc-100, and Luc-50. In addition, site-directed mutagenesis for an NF1 binding motif, which was located at the nucleotide positions between -438 and -427, was performed by a recombinant polymerase chain reaction (PCR) technique with use of Luc-447 as a template. The mutated NF1 primer used for PCR was generated by the sequential 3-oligonucleotide mutation at -429 to -427 as shown in Figure 5A, and the PCR product was sequenced and ligated into pGLB (designated Luc-447 MT).

View larger version (18K): [in this window] [in a new window]   Figure 5. Effect of a site-directed mutation disrupting a consensus sequence for NF1 on gadd153 gene transcription. A, Wild-type nucleotide sequence for NF1 binding motif and its point-mutated sequence (underlining). B, Relative luciferase activity of a wild-type (Luc-447) or point-mutated (Luc-447 MT) plasmid in VSMCs. Luciferase assay was performed as shown in Figure 2. Promoter activity was expressed as a relative activity to the value of Luc-447 that was set to unity. All data are expressed as mean±SE from 4 separated assays.

Transient DNA Transfection and Luciferase Assay
VSMCs were seeded in 60-mm dishes at a density of 5x10⁵ cells per dish 24 hours before transfection. Transient transfection was performed by Lipofectamine Plus (GIBCO-BRL) as described previously.¹⁵ Each gadd153 promoter/firefly luciferase fusion vector (2 µg per dish) was cotransfected into VSMCs together with 0.5 µg of pRL-CMV vector (Promega), which had a cytomegalovirus promoter in front of a renilla luciferase cDNA. After transfection, cells were incubated for an additional 48 hours. Luciferase assay was carried out according to the manufacturer’s specifications for the Dual-Luciferase Reporter Assay System (Promega), and the activity of renilla luciferase was used to correct for the variation of transfection efficiency. After sequential quantification of firefly and renilla luciferase activities in cell lysates, the promoter activity of each plasmid was calculated as a firefly/renilla luciferase activity ratio to obtain a relative activity.

EMSA and Supershift Assays
Nuclear protein extraction from proliferating VSMCs, electrophoretic mobility shift assay (EMSA), and supershift assay were carried out as described previously.¹⁶ The sequence spanning -447 through -358 was divided into five 30-bp segments, and double-stranded oligonucleotide probes (P1 to P5) were synthesized for these segments, as shown in Figure 3A. Two types of consensus sequences for NF1 were prepared as probes. One is a P1 probe containing an NF1 consensus sequence of the gadd153 gene. The other is a 25-bp double-stranded oligonucleotide probe containing an NF1 consensus sequence of the adenovirus 2 gene (aNF1, 5'-TTTTGGATTGAAGCCAATATGATAA-3'). Antiserum raised against recombinant CAAT-binding transcription factor (CTF)-2, which was readily interacted with CTF/NF1 proteins, was used for a supershift assay.

View larger version (15K): [in this window] [in a new window]   Figure 3. Sequences of oligonucleotide probes used for EMSA and results of EMSA with use of nuclear extracts from VSMCs. A, Sequence spanning -447 through -358 of the gadd153 gene was divided into five 30-bp segments, and double-stranded oligonucleotide probes (P1 to P5) were synthesized for these segments. B, End-labeled probes (P1 to P5) were incubated with nuclear extracts (2 µg) prepared from proliferating VSMCs, and each reaction mixture was analyzed on a 6% polyacrylamide gel (lanes 1 to 5). Lane 6 indicated only a 32P-labeled P1 probe. B1 indicates positions of specifically retarded bands; free, those of free probe.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Isolation of the 5'-Flanking Region of the Rat gadd153 Gene
One 12-kbp rat gadd153 genomic clone isolated from 1x10⁷ clones of the rat genomic library is shown in Figure 1. (The nucleotide sequence of the rat gadd153 gene reported in this study has been submitted to GenBank with accession No. AF314033.) A 1574-bp segment of the genomic sequence contained a 1480-bp 5'-flanking region and a 94-bp coding region of the gadd153 gene. Two transcription start sites were identified by the primer extension method from poly(A)⁺ RNAs (data not shown). The major start site with an adenine residue (A) and minor one with a thymidine residue (T) are indicated by asterisks. These data were completely identical to previous data of the hamster and human gadd153 genes.^{17 18} Hence, residue A was numbered as the nucleotide position +1 as shown in Figure 1.

View larger version (64K): [in this window] [in a new window]   Figure 1. Sequence alignments for a promoter region and its upstream cis-acting elements of the rat gadd153 gene (the nucleotide sequence of the rat gadd153 gene reported in this study has been submitted to GenBank with accession No. AF314033). Transcriptional start sites determined by primer extension analysis are indicated by asterisks, and major start site A is represented as the nucleotide position +1. A part of exon 1 is represented in boldfaced letters, and underlined sequences show notable cis-acting elements found in the 5'-flanking region. SP-1 indicates SP-1 element; AP-1, AP-1 element; ATF, activating transcription factor; GC, GC box; NF1, NF1 element; and TATA-like, variant of the TATA box.

Putative cis-Acting Elements Seen in 5'-Flanking Region of the Rat gadd153 Gene
A computer-assisted search for an exact match with well-defined transcriptional cis-acting elements revealed the presence of a TATA-like box at -32 bp, a GC box at -153 bp, an activator protein (AP)-1 element at -245 bp, 2 stimulatory protein (SP)-1 elements at -299 and -1480, a binding site for the nuclear factor for interleukin (IL)-6 (NF-IL6), which overlapped the activating transcription factor at -323 bp, 1 binding site for NF1 at -438 bp, 2 additional sites for NF-IL6 at -478 and -670 bp, and 1 enhancer core sequence for C/EBP, which overlapped with another NF-IL6 at -1113 bp.

Promoter Activity of the Rat gadd153 Gene in VSMCs
To assess a basal promoter activity of the rat gadd153 gene in VSMCs, luciferase assay was performed for the 8 plasmids, Luc-1,480 through Luc-50 (Figure 2). The deletion mutant Luc-367 showed the highest promoter activity, whereas the presence of the sequence spanning -447 and -368 drastically reduced the promoter activity to the level of promoterless plasmid, pGLB. In addition, promoter activity was markedly reduced between Luc-273 and Luc-191.

View larger version (14K): [in this window] [in a new window]   Figure 2. Plasmids used for luciferase assay and their relative promoter activity in VSMCs. Progressive 5' deletions, Luc-1,480 through Luc-50, had the nucleotide sequence starting at positions -1480, -1000, -447, -367, -273, -191, -100, and -50, respectively. Each plasmid (2 µg per dish) was cotransfected into VSMCs together with pRL-CMV vector (0.5 µg per dish) with use of Lipofectamine Plus. After 48 hours, luciferase assay was carried out by using the Dual-Luciferase Reporter Assay System, and the activity of renilla luciferase was used to correct for the variation of transfection efficiency. After sequential quantification of firefly and renilla luciferase activities in cell lysates, promoter activity of each plasmid was determined by the firefly/renilla luciferase ratio and was expressed as a relative activity to the value of Luc-1,480, which was set to 100%. All data are expressed as mean±SE from 4 separated assays.

Nuclear Factors That Bind to NRE of the gadd153 Promoter Region
A luciferase assay using 5' deletions indicated that an 80-bp segment between -447 and -368 negatively regulated a basal promoter activity of the gadd153 gene as an NRE. To identify the nuclear factors that actually bind to the NRE, EMSA was performed with the use of P1 to P5 probes (Figure 3B). Only P1 was shifted by nuclear extracts, generating a single band (lane 1). Because P1 contained a consensus sequence for NF1, an NF1-binding consensus probe, aNF1, was used for EMSA as a control probe (Figure 4). The aNF1 was also shifted by nuclear extracts, generating a single band (lane 5) to a position almost identical with that of P1 (lane 1). Competition experiments demonstrated that a 100-molar excess of either unlabeled P1 (lane 2) or aNF1 (lane 6) completely competed out each shifted band. To further determine the nature of DNA-binding proteins for P1 or aNF1, a supershift assay was performed by using antiserum against a recombinant CTF/NF1. The P1 and nuclear factor complex was markedly supershifted (lane 3) and the aNF1 complex was partially supershifted (lane 7) by antiserum, whereas both bands were not supershifted by preimmune rabbit serum (lanes 4 and 8).

View larger version (32K): [in this window] [in a new window]   Figure 4. Supershift assay using 2 types of consensus probe for NF1. Two types of NF1 consensus probe were used for the EMSA. These are P1 and aNF1 probes containing NF1 consensus sequence of the gadd153 and the adenovirus 2 gene, respectively. End-labeled P1 (lanes 1 to 4 and 9) or aNF1 (lanes 5 to 8) probe was incubated with nuclear extracts (2 µg) prepared from proliferating VSMCs. For competition experiments, a 100-molar excess of unlabeled P1 (lane 2) or aNF1 (lane 6) was incubated with nuclear extracts for 15 minutes before adding the corresponding labeled probe. Lanes 1 and 5 included no competitor, and lane 9 included no nuclear extracts. For supershift assay, 1 µL of specific antiserum against CTF/NF1 (lanes 3 and 7) or preimmune serum (lanes 4 and 8) was added to nuclear extracts before adding the labeled probe. Asterisk indicates supershifted bands; free, free probe. These data are representative of 3 separate experiments.

Effect of Site-Directed Mutagenesis for NF1 Binding Motif on Promoter Activity
To further clarify that gadd153 gene transcription was suppressed by an NRE, promoter activities were compared between a wild-type (Luc-447) and a point-mutated (Luc-447 MT) luciferase vector in VSMCs (Figure 5). Promoter activity of Luc-447 MT was markedly higher (14-fold) than that of Luc-447.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In the present study, we isolated a 5'-flanking region of the rat gadd153 gene to investigate the transcription regulatory mechanisms of the gadd153 gene in growing VSMCs and identified a specific transcriptional repressor, NF1, which mainly regulated a basal promoter activity of the gene via an NRE.

Comparison of promoter activity between Luc-273 and Luc-191 indicated that the region spanning -273 and -192 acted as a basal promoter or transcriptional activator of the gadd153 gene (Figure 2). Because this region has an AP-1 binding motif, AP-1 could drive a basal promoter activity of gadd153 gene expression in growing VSMCs. Indeed, Guyton et al¹⁹ have already demonstrated that oxidative stresses, including H₂O₂ and UV irradiation, rapidly induce gadd153 gene expression, which is mainly mediated by an AP-1 site in the hamster gadd153 gene. On the other hand, promoter activity was drastically decreased by the presence of an NRE spanning -447 and -368, which contained an NF1-binding motif. NF1 is a family of transcription factors encoded by at least 4 different genes: NF1-A, NF1-B, NF1-C (or CTF/NF1), and NF1-X. All isoforms share a highly conserved DNA-binding domain that recognizes a TTGGCN₅GCCAA sequence or single half sites (TTGGC or GCCAA).²⁰ NF1 can either activate or repress the initiation of various gene transcriptions. Whereas NF1 acts as a transcriptional silencer for the genes including GLUT4,²¹ growth hormone,²² and peripherin,²³ it acts as a transcriptional activator for the genes including elastin²⁴ and collagen ₁ (I).²⁵ In the present study, we have reported that NF1 acted as a negative regulator for gadd153 gene transcription via binding to an NRE seen in its promoter region. GADD153 proteins were originally isolated on the basis of its rapid induction by UV radiation in Chinese hamster ovary cells,^{26 27} and this expression was subsequently found to be inducible by a wide variety of DNA damaging agents and growth arrest treatments.^{6 7 8} GADD153, also known as C/EBP homologous protein-10 (CHOP-10), belongs to the family of basic region–leucine zipper class transcriptional factors, the C/EBP family.¹ The C/EBP family participates in the process of terminal differentiation and growth arrest in adipose tissue.¹ Recently, we reported that the C/EBP family is also involved in cell proliferation and apoptosis of VSMCs.^{13 15} Several studies have indicated that GADD153 is directly associated with the apoptosis induced by anticancer agents in many types of tumor cell lines, including ovarian cancer,²⁸ leukemia,²⁹ and prostatic cancer.³⁰ A direct relationship between GADD153 expression and apoptosis has been proven by the study of mice carrying null mutations in the gadd153/CHOP-10 gene. Mouse embryonic fibroblasts derived from CHOP-10-/- animals exhibited significantly less apoptosis on exposure to agents that perturb cellular functions of endoplasmic reticulum, such as tunicamycin and calcium ionophore A23187, compared with that of wild-type animals.³¹ The critical importance of GADD153 function is observed in the signaling cascade of apoptotic cells exposed to endoplasmic reticular stress. In response to endoplasmic reticular stress, GADD153 is induced and phosphorylated via a pathway involving p38 mitogen-activated protein kinase, and the phosphorylated protein can enhance the function or gene transcription of gadd153 itself.³² Furthermore, Brenner et al³³ have reported that Fas-induced apoptosis in human leukemic Jurkat cells is directly mediated by phosphorylation of GADD153 via p38 mitogen-activated protein kinase. Very recently, we determined that GADD153 expression was highly induced in the apoptotic VSMCs that were frequently observed in neointimal lesions of the balloon-injured carotid artery.¹³ All these observations indicate that the NF1 family acts as a transcriptional repressor of the gadd153 gene in VSMCs and probably acts as an antiapoptotic factor by continuing suppression of gadd153 gene expression in growing VSMCs.

	Acknowledgments

 
This work was supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (Nos. 11838012 and 12470155), from a Japanese Heart Foundation Grant for Research on Hypertension and Vascular Metabolism, and from the Takeda Medical Foundation. Antiserum raised against recombinant CTF-2 was generously provided by Dr Naoko Tanese, Department of Microbiology, New York University, NY.

	Footnotes

 
Reprint requests to Takafumi Okura, MD, The Second Department of Internal Medicine, Ehime University School of Medicine, Onsen-gun, Ehime 791-0295, Japan.

Received October 24, 2000; first decision November 30, 2000; accepted December 14, 2000.

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