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[Cancer Research 65, 4485-4489, June 1, 2005]
© 2005 American Association for Cancer Research

Priority Reports

Tumor Suppressor VDUP1 Increases p27kip1 Stability by Inhibiting JAB1

Jun-Ho Jeon1, Kee-Nyung Lee1, Chae Young Hwang2, Ki-Sun Kwon2, Kwan-Hee You3 and Inpyo Choi1

Laboratories of 1 Immunology and 2 Functional Proteomics, Korea Research Institute of Bioscience and Biotechnology, 3 School of Bioscience and Biotechnology, Chungnam National University, Yusong, Taejon, Republic of Korea

Requests for reprints: Inpyo Choi, Laboratory of Immunology, Korea Research Institute of Bioscience and Biotechnology, Yusong, 305-333 Taejon, Republic of Korea. Phone: 82-42-860-4223; Fax: 82-42-860-4593; E-mail: ipchoi{at}kribb.re.kr.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Vitamin D3 up-regulated protein 1 (VDUP1) is a stress-response gene that is up-regulated by 1,25(OH)2D3 in many cells. It has been reported that VDUP1 expression is reduced in many tumor cells and the enforced expression of VDUP1 inhibits cell proliferation by arresting cell cycle progression. Here, we found that VDUP1–/– fibroblast cells proliferated more rapidly compared with wild-type cells with reduced expression of p27kip1, a cyclin-dependent kinase inhibitor. JAB1 is known to interact with p27kip1 and to decrease the stability of p27kip1. VDUP1 interacted with JAB1 and restored JAB1-induced suppression of p27kip1 stability. In this process, VDUP1 blocked the JAB1-mediated translocation of p27kip1 from the nucleus to the cytoplasm. In addition, VDUP1 inhibited JAB1-mediated activator protein-1 activation and cell proliferation. Taken together, these results indicate that VDUP1 is a novel factor of p27kip1 stability via regulating JAB1.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Absent or reduced expression of the cyclin-dependent kinase inhibitors has been observed in many malignant tumors (1–4). p27kip1 protein level is frequently reduced in a remarkably wide range of human tumors, including lymphomas and carcinomas of various tumors (5, 6). A recent report indicates that p27kip1 has central role in tumor suppression in the highly cooperative manner with p53 in vivo (7). It is well known that p27kip1 protein levels are mainly regulated through degradation by ubiquitin-dependent proteolysis (8). In tumors, low p27kip1 level was attributed to increased rates of proteasome-mediated degradation or aberrant localization to the cytoplasm (9, 10). For translocation of p27kip1, JAB1 interacting with p27kip1 causes the translocation of p27kip1 from the nucleus to the cytoplasm (11). Regulation of interacting p27kip1 and JAB1 is one of critical processes in tumor progression.

Vitamin D3 up-regulated protein 1 (VDUP1) was originally identified as a differentially expressed gene in 1{alpha},25-dihydroxyvitamin D3 [1,25(OH)2D3]–treated HL-60 leukemia cells (12) and is a component of transcriptional repressors. It interacts with promyelocytic leukemia zinc finger, Fanconi anemia zinc finger, and histone deacetylase 1 to suppress the promoter activity of cyclin A2 and IL-3 receptors (13). In addition, VDUP1 interacts with an antioxidant gene, thioredoxin (Trx), to inhibit the reducing activity of Trx and to block the interaction of Trx with other factors, such as ASK-1 and PAG (14, 15). VDUP1 expression was also induced when the cell cycle was blocked by growth arrest stimuli (14). The enforced expression of VDUP1 inhibited tumor cell growth and cell cycle progression, indicating that VDUP1 is a novel tumor suppressor (13). Clinically, VDUP1 is related to tumorigenesis and its expression is dramatically reduced in various tumor tissues, including breast and lung cancers.

In this paper, we found that VDUP1 is involved in JAB1-mediated regulation of p27kip1 stability. p27kip1 expression was reduced in VDUP1–/– cells and overexpression of VDUP1 restored the JAB1-induced p27kip1 suppression. Furthermore, VDUP1 interacted with JAB1 to block the JAB1-mediated translocation of p27kip1.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Cell culture. NIH 3T3, 293, and lung fibroblast cells were maintained in DMEM supplemented with 10% fetal bovine serum, L-glutamine, penicillin, and streptomycin. Fibroblast cells were subcultivated 3 x 105 cells/dish every 3 days according to the 3T3 protocol (16). For transient transfection assays, cells grown in 100 mm dishes were transfected with appropriate expression plasmids using the calcium phosphate or Lipofectamine (Life Technologies, Grand Island, NY) according to the manufacturer's protocol. All antibodies were purchased from Becton Dickinson-Pharmingen (San Diego, CA), Santa Cruz Biotechnologies (Santa Cruz, CA), Sigma Chemical, Co. (St. Louis, MO), MBL (Nagoya, Japan), and Invitrogen (Carlsbad, CA).

Reverse transcription-PCR analysis. Total RNA was extracted using RNAzol B (Tel-Test, Friendswood, TX) according to the manufacturer's instructions. For reverse transcription-PCR analysis, 3 µg of total RNA was transcribed with 0.5 µg of random primer using reverse transcriptase (Promega, Madison, WI) at 37°C for 1 hour. For the amplification of mouse VDUP1 and p27, PCR was done with following primers: mouse VDUP1, 5'-CATGAGGCCTGGAAACAAAT-3' and 5'-GCCATTGGCAAGGTAAGTGT-3'; mouse p27, 5'-GGATGGACGCCAGACAAG-3' and 5'-GGGGAACCGTCTGAAACATT-3'; mouse ß-actin, 5'-GTGGGCCGCTCTAGGCACCAA-3' and 5'-CTTTGATGTCACGCACGATTTC-3'.

Electrophoretic mobility shift assay. Nuclear extracts were prepared from lung fibroblast cells treated with tumor necrosis factor-{alpha} (TNF-{alpha}; 20 ng/mL) for 2 hours. Electrophoretic mobility shift assay (EMSA) was done using a consensus activator protein-1 (AP-1) oligonucleotide (Promega) for the binding of AP-1. Radioactive double-stranded oligonucleotides labeled with T4 polynucleotide kinase and [{gamma}-32P]ATP were incubated with nuclear extracts (5 µg) for 20 minutes in gel shift binding buffer [10 mmol/L Tris-HCl (pH 7.5), 50 mmol/L NaCl, 1 mmol/L DTT, 1 mmol/L EDTA, 5% glycerol, 2 µg poly(deoxyinosinic-deoxycytidylic acid), and 1 µg bovine serum albumin (BSA)] in the presence or the absence of antibodies for 20 minutes at room temperature. Then radiolabeled probe (≥20,000 cpm) was added to the reaction mixture for an additional 10 minutes at room temperature. The binding products were electrophoresed at 4 to 5 V/cm on 6% polyacrylamide gel in 0.5x Tris-borate EDTA buffer. The gel was dried and analyzed by autoradiography.

Western blot and immunoprecipitation. The 293 cells were transfected with various combinations of expression vectors, as indicated in the text. Twenty-four hours after transfection, cells were harvested and lysed in lysis buffer [20 mmol/L HEPES (pH 7.9), 100 mmol/L KCl, 300 mmol/L NaCl, 10 mmol/L EDTA, 0.1% Nonidet P-40, plus protease inhibitors] for 1 hour. After lysis, aliquots of cell lysates were incubated with glutathione-Sepharose (Pharmacia, Piscataway, NJ) or protein G (Pharmacia) for 2 hours at 4°C. These beads were then washed five times with lysis buffer. The proteins were recovered by boiling in SDS-PAGE sample buffer. The eluted proteins were separated on SDS-PAGE, and transferred to polyvinylidene difluoride membrane (Bio-Rad, Hercules, CA). The blot was subjected to Western blot analysis with anti-Flag, antihemagglutinin and anti–{alpha}-tubulin (Sigma) antibody, anti-p27 antibody (Becton Dickinson-PharMingen), anti–glutathione S-transferase (GST) antibody (Molecular Probes, Eugene, OR), anti-myc antibody (Invitrogen), anti-VDUP1 (MBL), anti-JAB1, anti-RB (Oncogene, San Diego, CA), anti–cyclin D1, anti–cyclin E, anti-P15, and anti-P16 antibody (Santa Cruz) using an enhanced chemiluminescence system (Amersham Pharmacia).

Immunofluorescence microscopy. Forty-eight hours after transfection, 293 cells were detached from dishes and transferred onto sterile glass slides. Cells grown on glass slides were washed with PBS, dried, and fixed for immunostaining using a freshly prepared solution of cold methanol/acetone (1:1) for 20 minutes. After fixation, cells were dried and incubated in blocking buffer (1% BSA in PBS) for 20 minutes. Cells were incubated with either anti-Flag M2 monoclonal antibody (mAb; Sigma) or antihemagglutinin mAb (Sigma) at 1/100 dilution in blocking buffer for 1 hour and washed five times with PBS. Cells were incubated with goat Texas red–conjugated anti-mouse IgG (Becton Dickinson-PharMingen) at 1/200 dilution in blocking buffer for 30 minutes and were extensively washed again with PBS. For all staining, cells were incubated with 0.1 µg/mL of 4,6-diamidino-2-phenylindole (DAPI; Sigma) to stain the nuclei. Cells were mounted with mounting solution (DAKO, Glostrup, Denmark). Samples were examined on a LSM510 confocal microscope (Carl Zeiss, Gottingen, Germany).

Luciferase reporter assay. pAP1-Luc plasmid (Stratagene, La Jolla, CA) was transfected into 293 cells by using Lipofectamine (Life Technologies). In addition, 293 cells were cotransfected with the Renilla luciferase control vector (Promega) to monitor the transfection rates. Determination of firefly and Renilla luciferase activities was done using the Dual-Luciferase Reporter Assay System (Promega). Briefly, the cells were washed with PBS and lysed with passive lysis buffer. Cell lysates were mixed with Luciferase Assay Reagent II, and the firefly luminescence was measured using a luminometer (Turner Designs, Sunnyvale, CA). Next, samples were mixed with the stop reagent and the Renilla luciferase activity was measured as an internal control. Relative luciferase activity was calculated as the ratio of firefly luciferase activity to Renilla luciferase activity.

Bromodeoxyuridine incorporation. NIH 3T3 cells transfected with JAB1 or control plasmid were cotransfected with EGFP or VDUP1 EGFP. Cells were starved for 24 hours and then incubated with bromodeoxyuridine (BrdUrd) for 18 hours and stained with anti-BrdUrd mAb (Oncogene) and Texas red–linked anti-mouse IgG (Becton Dickinson-PharMingen). Cell samples were analyzed by phase-contrast or fluorescence microscopy. More than 500 cells were counted for each transfection.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Our previous study showed that the enforced expression of VDUP1 in tumor cells induced the inhibition of cell proliferation and cell cycle arrest at G1-G0(13). VDUP1–/– mice have been generated by replacing exon 1 to exon 8 of VDUP1 with neo cassette gene (17). To investigate the roles of VDUP1 in cell growth VDUP1–/– cells, the proliferation of lung fibroblast cells from VDUP1–/– mice was monitored (Fig. 1A). VDUP1–/– lung fibroblast cells grew more rapidly compared with wild-type (WT) lung fibroblast cells (passage numbers 4-10). Cell cycle analysis showed that the S phase of VDUP1–/– lung fibroblast cells increased about 2-fold compared with that of WT cells (16.25% versus 8.43%).



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  		Figure 1. Cell proliferation and the expression of cell cycle regulators in VDUP1–/– cells. A, RT-PCR analysis of WT and VDUP1–/– lung fibroblast cells (left). Lung fibroblast cells (passage numbers 4-10) from WT and VDUP1–/– mice were incubated for the indicated times, and cell numbers were counted (right). B, Western blot (top) and RT-PCR (bottom) analysis of p27kip1 expression in WT and VDUP1–/– lung fibroblasts. C, Western blot analysis of p27kip1 expression in 48 hours serum-starved WT and VDUP1–/– lung fibroblasts. D, Western blot analysis of cell cycle regulators in WT and VDUP1–/– lung fibroblast cells.

 
Next, we did Western blot analysis to examine the possible roles of cell cycle regulators, including p27kip1, proliferating cell nuclear antigen, PTEN, and smad4, in VDUP1-mediated proliferation. Among them, p27kip1 expression was most strongly reduced in VDUP1–/– lung fibroblast cells (Fig. 1B). However, the mRNA level of p27kip1 was not changed, indicating that the reduction of p27kip1 was a posttranscriptional event. It has been previously reported that the expression of p27kip1 is up-regulated by serum starvation (18). Thus, we next investigated whether expression of p27kip1 is increased by serum starvation in VDUP–/– lung fibroblasts. Although the p27kip1 expression was moderately increased in VDUP–/– lung fibroblasts, the level of p27kip1 was much lower than that of WT after serum starvation (Fig. 1C). In addition, the expression of other cell cycle regulators was moderately changed. For example, the expression of other cell cycle inhibitors, such as p16, RB, and p130, was decreased (Fig. 1D). However, the expression of cyclins (cyclin E and cyclin D1) and E3 ubiquitin ligase SKP2 was increased. SKP2 has been known to regulate p27kip1 degradation (19).

It is known that p27kip1 stability was controlled by JAB1, which induced the translocation of p27kip1 from the nucleus to the cytoplasm (11). When JAB1 cDNA was cotransfected into 293 cells with p27kip1 cDNA, p27kip1 protein expression was reduced as reported (Fig. 2A). Additional transfection of VDUP1 cDNA restored the JAB1-mediated suppression of p27kip1 protein expression. The restoration of endogenous p27kip1 protein expression was also observed by transfection of VDUP1 cDNA (Fig. 2B). VDUP1 alone increased p27kip1 protein expression moderately (Fig. 2B). Next, the possible physical interaction between VDUP1 and JAB1 was tested. GST pull-down assay showed that VDUP1 physically interacted with JAB1 (Fig. 2C). Serially deleted mutation analysis indicated that the COOH terminal of VDUP1 is critical for binding of JAB1. In addition, immunoprecipitation assay for the endogenous protein interaction showed that endogenous VDUP1 interacted with JAB1 directly (Fig. 2D).



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  		Figure 2. VDUP1 restored JAB1-mediated suppression of p27kip1 stability by interacting with JAB1. Restoration of protein level of transfected p27kip1 (A) and endogenous p27kip1 (B) by VDUP1. After transfection with indicated plasmids, NIH 3T3 cells were lysed and subjected to Western blot analysis with anti-p27kip1, anti-GST, anti-Flag, anti–myc antibody, and anti–{alpha}-tubulin antibody. The GST expression vector was used as transfection efficiency control. C, VDUP1 interacts with JAB1 in vivo. pEBG, pEBG-VDUP1, NH2-terminal–deleted VDUP1 (pEBG-VDUP1 148-396 and 254-396 aa), and COOH-terminal–deleted VDUP1 (pEBG-VDUP1 1-120 aa) plasmids were transiently transfected into 293 cells, and the cell lysates were subjected to precipitation with glutathione-Sepharose beads. Proteins precipitated were analyzed by Western blot using anti-GST or anti-Flag antibody, respectively. D, endogenous interaction between VDUP1 and JAB1. Immunoprecipitation was done using anti-JAB1 and immunoprecipitates were again analyzed by Western blotting using anti-VDUP1 antibody.

 
JAB1 was initially identified as a coactivator of c-Jun as a subunit of COP9 signalosome. VDUP1 inhibited JAB1-mediated AP-1 activation in a dose-dependent manner (Fig. 3A). It is known that TNF-{alpha} activates AP-1 activity. VDUP1 also inhibited TNF-{alpha}–mediated AP-1 activation similarly as shown in case of JAB1-mediated activation (Fig. 3B). In addition, VDUP1 inhibited JAB1-induced cell growth as monitored by BrdUrd incorporation (Fig. 3C). These data indicate that VDUP1 is a functional inhibitor of JAB1 by interacting physically. We next investigated whether AP-1 activity was affected in VDUP1–/– fibroblast. EMSA analysis showed that AP-1 DNA binding activity was increased in VDUP1–/– fibroblasts (Fig. 3D). In addition, AP-1 reporter activity was higher in VDUP1–/– fibroblasts than WT fibroblasts as monitored by AP-1 reporter assay (Fig. 3E). Collectively, these data indicated that VDUP1 represses JAB1-induced AP-1 activity.



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  		Figure 3. VDUP1 inhibited JAB1-mediated transcription activation and proliferation. A, VDUP1 inhibited JAB1-mediated (left) or JAB1 and c-Jun–mediated (right) activation of AP-1 reporter activity in 293 cells. 293 cells were transiently transfected with 10 ng of pcDNA 3.1 c-Jun, 0.5 µg of pflag-JAB1, different amounts of pflag-VDUP1 (1, 2, and 3 µg), and the AP-1 luciferase reporter plasmid. The total DNA concentration in each transfection was kept constant by adjusting with the empty vector. B, VDUP1 inhibited TNF-{alpha}–mediated activation of AP-1 reporter activity in 293 cells. 293 cells were transfected with 0.5 µg of pflag-JAB1, different amounts of pflag-VDUP1 (1, 2, and 3 µg), and the AP-1 luciferase reporter plasmid. The total DNA concentration in each transfection was kept constant by adjusting with the empty vector. Cells were treated or not with 10 ng/mL TNF-{alpha}. C, VDUP1 inhibited JAB1-mediated BrdUrd incorporation. NIH3T3 cells were transfected with pEGFP, pflag-JAB1, pEGFP-VDUP1, or cotransfected with pflag-JAB1 and pEGFP-VDUP1 plasmid. Cells were starved for 24 hours, incubated with BrdUrd for 18 hours, and stained with anti-BrdUrd and anti-Flag antibodies. Percentages of BrdUrd-positive cells among EGFP- or Flag-positive cells are shown. D, AP-1 DNA binding activity was increased in TNF-{alpha} (20 ng/mL)–treated VDUP1–/– fibroblast cells compared with WT fibroblast cells. Supershift analysis was done using c-Jun and c-Fos antibody as described in Materials and Methods. F, AP-1 luciferase activity was increased in JAB1-transfected VDUP1–/– fibroblast cells compared with WT fibroblast cells (top). Flag-JAB1 was transfected into WT and VDUP1–/– fibroblast cells and monitored by Western blot (bottom).

 
To understand molecular mechanism of VDUP1-mediated p27kip1 stability, the intracellular translocation of p27kip1, which was known to be controlled by JAB1, was monitored in the presence of VDUP1. p27kip1 was stably located in the nucleus (Fig. 4, left). Ectopic expression of JAB1 induced translocation of p27kip1 from the nucleus to the cytoplasm (Fig. 4, middle). However, VDUP1 blocked the translocation of p27kip1 to the cytoplasm, which was induced by JAB1 (Fig. 4, right). These data indicate that VDUP1 increases p27kip1 accumulation in the nucleus by inhibiting JAB1 to increase p27kip1 stability.



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  		Figure 4. VDUP1 blocked p27kip1 nuclear export mediated by JAB1. Subcellular localization of p27kip1 in 293 cells transfected with HA-p27kip1, JAB1, and VDUP1 as indicated. The p27kip1 images are shown in the first row, DAPI images are in the second row, and merged images of p27kip1 and DAPI are in third row. VDUP1 (GFP) and JAB1 (Texas red) expression was monitored in the fourth row.

 
Low or absent expression of p27kip1 serves as an excellent marker for many aggressive tumors (20, 21). The aberrant expression of p27kip1 is mainly due to protein destabilization. Protein levels of p27kip1 are mainly regulated by ubiquitin-dependent proteolysis (8). During this process, JAB1 binds to cause the translocation of p27kip1 from the nucleus to the cytoplasm to accelerate its degradation (11). Recently, it was reported that 1,25(OH)2D3 increases p27kip1 stability (22); vitamin D receptor is involved in this process (23). In advanced hyperparathyroidism, the reduced expression of p27kip1 and vitamin D receptor is a major pathogenic factor for nodular parathyroid gland growth (24). According to our observations, VDUP1 acts as a negative regulator for JAB1-dependent p27kip1 translocation and degradation. These observations imply that reduced level of VDUP1 in tumors confers low stability of p27kip1 protein, which is one of the key processes for tumorigenesis, and interacting with VDUP1 and JAB1 can be a another target event for modulating this process.


   Acknowledgments
 
Grant support: Grant FG-3-1-04 (I. Choi) of 21C Frontier Functional Human Genome Project from Ministry of Science and Technology and grant SC13040 (I. Choi) of 21C Frontier Stem Cell Research Project, Republic of Korea.

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.

Received 6/27/04. Revised 3/23/05. Accepted 3/31/05.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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N. Yabuta, H. Onda, M. Watanabe, N. Yoshioka, I. Nagamori, T. Funatsu, S. Toji, K. Tamai, and H. Nojima
Isolation and characterization of the TIGA genes, whose transcripts are induced by growth arrest
Nucleic Acids Res., October 18, 2006; 34(17): 4878 - 4892.
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 Clin. Cancer Res.Home page
K.-H. Shin, M. K. Kang, R. H. Kim, R. Christensen, and N.-H. Park
Heterogeneous Nuclear Ribonucleoprotein G Shows Tumor Suppressive Effect against Oral Squamous Cell Carcinoma Cells.
Clin. Cancer Res., May 15, 2006; 12(10): 3222 - 3228.
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C. M. Banwell, D. P. MacCartney, M. Guy, A. E. Miles, M. R. Uskokovic, J. Mansi, P. M. Stewart, L. P. O'Neill, B. M. Turner, K. W. Colston, et al.
Altered nuclear receptor corepressor expression attenuates vitamin d receptor signaling in breast cancer cells.
Clin. Cancer Res., April 1, 2006; 12(7): 2004 - 2013.
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