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Advances in Brief |
Program in Cellular and Molecular Biology [K. M. H., E. R. F.], Department of Molecular, Cellular, and Developmental Biology [D. Y-S. C.], Comprehensive Cancer Center [E. R. F.], and Departments of Internal Medicine, Human Genetics, and Pathology [E. R. F.], University of Michigan Medical School, Ann Arbor, Michigan 48109
| ABSTRACT |
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| Introduction |
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EF1/ZEB-1 (7)
, and SIP1/ZEB-2 (5)
, and the basic helix-loop-helix factor E12/E47 (8)
. The specific factors that repress E-cadherin likely vary depending on cell type and context. Additionally, the various E-cadherin repression factors described to date may act alone or in concert, and there may be other currently undefined factors required for transcriptional silencing of E-cadherin in cancer cells. The goal of the studies described here was to determine the specific promoter element(s) and factor(s) critical for repression of E-cadherin in breast carcinomas. We found both SNAIL and its family member SLUG to be capable of repressing E-cadherin in epithelial cells via the E-box elements in the proximal E-cadherin promoter. However, SLUG expression showed a much stronger correlation with loss of E-cadherin in breast cancer cell lines than did SNAIL expression, suggesting SLUG is a likely in vivo repressor of E-cadherin expression in breast carcinoma. | Materials and Methods |
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Plasmids.
Luciferase reporter gene constructs containing wild-type Ecadherin promoter sequences were described in detail previously (2
, 9) . Briefly, E-cadherin promoter sequences were amplified by PCR and cloned into the pGL2-Basic vector (Promega Corp., Madison, WI) upstream of firefly Luciferase. In all of the reporter gene constructs, the endogenous initiating methionine of the E-cadherin gene, located at bp +125, has been destroyed, and an additional 33 bp of flanking sequence separate E-cadherin promoter sequences from the Luciferase initiating methionine. PCR-based site-directed mutagenesis was used for the generation of reporter gene constructs with E-box mutations. All of the mutant constructs were made within the context of the reporter gene construct Ecad(-108)-Luc, which contains E-cadherin promoter sequences from -108 to +125 of the endogenous E-cadherin gene upstream of firefly Luciferase. E-box elements were mutated from 5'-CANNTG-3' to 5'-AANNTA-3' (sense strand). Full-length cDNAs for human SLUG and SNAIL were amplified from cell line RNA by reverse transcription-PCR, and a COOH-terminal flag epitope tag was added by PCR. Constructs were subcloned into the retroviral expression vector pPGS-CMV-CITE-neo (gift of G. Nabel, NIH, Bethesda, MD). For the generation of vectors encoding SLUG- and SNAIL-ER fusion proteins, SLUG and SNAIL cDNAs were cloned into the pBabePuro plasmid (gift of A. Friedman, Johns Hopkins University, Baltimore, MD) upstream of a modified mouse ER
ligand-binding domain. The identities of all plasmid inserts and vector boundary regions were confirmed by sequence analysis. The pCH110 plasmid contains a functional lacZ gene expressed under the control of the SV40 early promoter (Amersham Biosciences, Piscataway, NJ).
Reporter Gene Assays.
Cell lines growing at
70% confluence in six-well plates were transfected using FuGene6 (Roche Molecular Biochemicals) according to the manufacturers protocol. For experiments assessing activation of E-cadherin reporter gene constructs by endogenous factors, 0.8 µg E-cadherin reporter gene construct and 0.8 µg pCH110 were transfected per well. For experiments to determine the effects of SLUG and SNAIL on E-cadherin reporter gene activity, 1 µg effector plasmid (empty expression vector, SLUG expression vector, or SNAIL expression vector), 0.5 µg E-cadherin reporter gene construct, and 0.5 µg pCH110 were transfected per well. Experiments on the dose-dependent repression of E-cadherin reporter gene constructs by SLUG and SNAIL used 0.15 µg reporter construct, 0.35 µg pCH110, and increasing amounts of effector plasmid. In these dose-response studies, the total amount of transfected DNA was kept constant by adding empty expression vector as necessary. Cell extracts were prepared 3640 h after transfection using reporter lysis buffer (Promega Corp.) followed by determination of luciferase and ß-galactosidase activities. ß-Galactosidase activity was used to normalize for transfection efficiency.
Northern Blotting.
Total RNA was isolated from cells using TRIzol reagent (Invitrogen Corp.). Electrophoretic separation and membrane transfer of RNA were carried out by standard methods. For use as probes, E-cadherin, SLUG, SNAIL, and GAPDH cDNA fragments were labeled with [32P]dCTP (Amersham Biosciences) by random priming with the RediPrime II kit (Amersham Biosciences). Prehybridization and hybridization were carried out in Rapid-Hyb buffer (Amersham Biosciences), the membrane was washed, and the blot was exposed to BioMax MS film (Kodak, Rochester, NY).
Antibody Production.
GST fusion proteins were generated by subcloning cDNA sequences corresponding to the amino half of either SLUG (amino acids 1151) or SNAIL (amino acids 1146) into the vector pGEX-2T (Amersham Biosciences). Plasmids were introduced into the Escherichia coli strain BL21, and a large-scale preparation of recombinant protein was performed. After sonication of the bacteria, the fusion protein-containing supernatant was collected by centrifugation. GST fusion proteins were purified from this supernatant on a glutathione Sepharose 4B (Amersham Biosciences) column. Purified recombinant GST-SLUG protein was used directly as antigen for antibody production. Purified recombinant GST-SNAIL protein was separated by electrophoresis on a SDS-polyacrylamide gel, and the band corresponding to full-length GST-SNAIL was excised and used as antigen. Rabbit injection and serum collection were carried out by Covance Research Products Inc. (Richmond, CA). Serum was ammonium sulfate precipitated and then used either directly (anti-SNAIL antibodies) or purified (anti-SLUG antibodies) against a recombinant maltose-binding protein (MBP) fusion protein using the AminoLink Plus Immobilization kit (Pierce, Rockford, IL). Recombinant MBP-SLUG was generated by subcloning cDNA sequences corresponding to the amino half of SLUG (amino acids 1151) into the plasmid pMAL-c2 (New England Biolabs, Inc., Beverly, MA), inducing recombinant protein expression and purifying the MBP-SLUG on a column of amylose resin (New England Biolabs, Inc.).
Immunoblotting.
Whole cell lysates were prepared in radioimmunoprecipitation assay buffer [150 mM NaCl, 0.5% deoxycholic acid, 0.1% SDS, 1% NP40, 50 mM Tris (pH 8.0)] with Complete protease inhibitors (Roche Molecular Biochemicals). Approximately 35 µg of total protein per sample were separated by electrophoresis on SDS-polyacrylamide gels and transferred to Immobilon P membranes (Millipore Corp., Bedford, MA) by semi-dry electroblotting (Transblot; Bio-Rad Laboratories, Hercules, CA). Primary antibodies and the dilutions used were as follows: mouse monoclonal anti-flag M2 (Sigma Chemical Co.), 1:5,000; mouse monoclonal antibody HECD-1 against E-cadherin (Zymed Laboratories, Inc., San Francisco, CA), 1:5,000; rabbit polyclonal antibody A2066 against ß-actin (Sigma Chemical Co.), 1:1,000; rabbit polyclonal anti-SNAIL, 1:2,000; and rabbit polyclonal anti-SLUG, 1:800. Secondary antibodies and the dilutions used were as follows: horseradish peroxidase-conjugated goat antimouse IgG antibody (Pierce), 1:20,000; horseradish peroxidase-conjugated donkey antirabbit IgG antibody (Pierce); 1:20,000 for antiactin blots; and 1:80,000 for anti-SNAIL and anti-SLUG blots. Antibody complexes were detected using Western Blot Chemiluminescence Reagent Plus (NEN Life Science Products, Boston, MA) followed by exposure to X-OMAT AR film (Kodak).
| Results and Discussion |
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2-fold derepression of E-cadherin reporter gene activity in Ecad- breast cancer cell lines, with no effect on activity in Ecad- breast cancer cell lines (data not shown). EboxB, the central of the three E-box elements, did not appear to significantly modulate E-cadherin gene transcription in either Ecad- or Ecad+ breast cancer cell lines (Fig. 1C)
The three E-box elements in the proximal E-cadherin promoter are of a specific subclass of E-boxes; all contain the sequence 5'-CACCTG-3'. The sequence 5'-CACCT-3' is known to bind members of the
EF1 zinc-finger transcription factor family, including
EF1/ZEB-1 and SIP1/ZEB-2. Both
EF1/ZEB-1 and SIP1/ZEB-2 have been proposed to repress E-cadherin transcription (5
, 7)
. These factors are characterized by a protein domain structure in which a central homeodomain is flanked by NH2- and COOH-terminal clusters of zinc-fingers, so that one monomer can bind to bipartite DNA elements (10)
. The SIP1/ZEB-1 protein has been proposed to repress Ecadherin transcription by simultaneously interacting with both EboxA and EboxB in the proximal promoter (5)
. Thus, our finding that EboxB is not critical in regulating E-cadherin transcription in breast cancer cell lines (Fig. 1C)
may be of some significance. Given the likelihood that the EboxB mutation we created abolished SIP1/ZEB-1 binding, either SIP1/ZEB-1 is not a critical factor in the repression of E-cadherin in breast cancer or EboxB is not a necessary target for the binding of one zinc-finger of SIP1/ZEB-1 to the E-cadherin promoter.
Both SLUG and SNAIL Repress E-Cadherin in Vitro.
We next sought to identify and characterize specific proteins that may bind to the E-box elements in the proximal E-cadherin promoter and repress transcription in breast cancer. In light of the established roles of Slug and Snail in the down-regulation of E-cadherin during epithelial-mesenchymal transitions in development (11
, 12)
and the recent suggestion that SNAIL represses E-cadherin transcription in carcinomas (4)
, we focused on the role of these factors in the repression of E-cadherin in breast cancer. SLUG and SNAIL belong to the larger Snail family of proteins, and contain an NH2-terminal repression domain and a COOH-terminal zinc-finger DNA-binding domain (13)
.
Constructs expressing full-length, flag epitope-tagged SLUG and SNAIL were generated (Fig. 2A)
, and the effects of these proteins on E-cadherin reporter gene activity were assessed. When compared with the effects of the empty expression vector on E-cadherin reporter gene activity, both SLUG and SNAIL repressed the wild-type E-cadherin reporter construct in Ecad+ breast cancer cell lines (Fig. 2B)
. However, neither SLUG nor SNAIL could repress a construct in which all three of the E-box elements were mutant (Fig. 2C)
. Additionally, both SLUG and SNAIL demonstrated dose-dependent repression of the wild-type E-cadherin reporter gene construct Ecad(-108)-Luc in the Ecad+ breast cancer cell line MCF-7 (Fig. 2D)
. Taken together, these data show that SLUG and SNAIL are capable of repressing E-cadherin transcription in vitro, and this repression is mediated via the E-box elements in the proximal E-cadherin promoter.
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. The ligand-binding domain contains a mutation that renders it resistant to binding by endogenous estrogens yet capable of binding to the synthetic ligand 4-OHT (14)
. Chimeric proteins are constitutively expressed but inactive in the absence of ligand and activated after the exposure of cells to 4-OHT. Constructs expressing SLUG-ER and SNAIL-ER fusions were generated. Stable clones of rat kidney epithelial RK3E cells expressing one of the chimeric proteins were obtained, and expression of the chimeric proteins was confirmed (Fig. 3A)
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Endogenous SLUG Expression Is Correlated with a Loss of E-Cadherin Transcription.
Because both SLUG and SNAIL were capable of repressing E-cadherin promoter activity and endogenous E-cadherin expression, we sought to characterize expression of SLUG and SNAIL in breast cancer cell lines by Northern blot analysis. Expression of SLUG, rather than that of SNAIL, was strongly correlated with the absence of E-cadherin transcripts (Fig. 4)
. The data imply SLUG is the more likely in vivo repressor of E-cadherin transcription in breast cancer. In cell lines analyzed for their ability to activate E-cadherin reporter gene activities, E-cadherin promoter activities were reduced in lines with SLUG expression (Fig. 1B
; data not shown). However, a tight correlation between the relative levels of endogenous SLUG transcripts and E-cadherin promoter activity was not observed in the three Ecad- cell lines studied, perhaps because SLUG protein levels may not be strictly tied to transcript levels, and differences in the expression of other proteins from one line to another may affect the ability of SLUG to repress E-cadherin transcription. A fraction of the cell lines studied showed seemingly discordant results in regard to SLUG and E-cadherin expression patterns (i.e., SK-BR-3, MDA-MB-468, and BT-20; Fig. 4
). Therefore, additional studies were carried out to clarify the relationship between SLUG and E-cadherin in the three lines.
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In closing, we would emphasize that our findings demonstrate the E-box elements, specifically EboxA and EboxC, contained in the proximal E-cadherin promoter appear critical in repression of E-cadherin gene transcription in breast cancer. Whereas SLUG and SNAIL were found to be capable of repressing E-cadherin gene transcription via these E-box elements, our data indicate that SLUG is a more likely in vivo repressor in breast cancer. Given the sizable number of potential transcriptional repressors thus far implicated in the repression of E-cadherin gene transcription (4 , 5 , 7 , 8) , it is possible that different factors function in the repression of E-cadherin in different settings. Alternatively, multiple factors may collaborate in mediating repression in vivo. Additional studies should help in resolving the remaining uncertainties about the mechanisms by which SLUG and other factors repress E-cadherin expression in breast and other cancers.
| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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1 Supported in part by NIH Grant T32 CA09676. ![]()
2 To whom requests for reprints should be addressed, at Division of Medical Genetics, University of Michigan Medical Center, 4301 MSRB3, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0638. Phone: (734) 764-1549; Fax: (734) 647-7979; E-mail: fearon{at}umich.edu ![]()
3 The abbreviations used are: ER, estrogen receptor; 4-OHT, 4-hydroxytamoxifen; Ecad+, intact E-cadherin transcription; Ecad-, defective E-cadherin transcription; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GST, glutathione S-transferase. ![]()
Received 12/ 3/01. Accepted 1/22/02.
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M. Takkunen, R. Grenman, M. Hukkanen, M. Korhonen, A. Garcia de Herreros, and I. Virtanen Snail-dependent and -independent Epithelial-Mesenchymal Transition in Oral Squamous Carcinoma Cells J. Histochem. Cytochem., November 1, 2006; 54(11): 1263 - 1275. [Abstract] [Full Text] [PDF] |
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Y. Hayashida, Y. Urata, E. Muroi, T. Kono, Y. Miyata, K. Nomata, H. Kanetake, T. Kondo, and Y. Ihara Calreticulin Represses E-cadherin Gene Expression in Madin-Darby Canine Kidney Cells via Slug J. Biol. Chem., October 27, 2006; 281(43): 32469 - 32484. [Abstract] [Full Text] [PDF] |
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G. Moreno-Bueno, E. Cubillo, D. Sarrio, H. Peinado, S. M. Rodriguez-Pinilla, S. Villa, V. Bolos, M. Jorda, A. Fabra, F. Portillo, et al. Genetic Profiling of Epithelial Cells Expressing E-Cadherin Repressors Reveals a Distinct Role for Snail, Slug, and E47 Factors in Epithelial-Mesenchymal Transition Cancer Res., October 1, 2006; 66(19): 9543 - 9556. [Abstract] [Full Text] [PDF] |
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R. A. Winn, M. Van Scoyk, M. Hammond, K. Rodriguez, J. T. Crossno Jr., L. E. Heasley, and R. A. Nemenoff Antitumorigenic Effect of Wnt 7a and Fzd 9 in Non-small Cell Lung Cancer Cells Is Mediated through ERK-5-dependent Activation of Peroxisome Proliferator-activated Receptor {gamma} J. Biol. Chem., September 15, 2006; 281(37): 26943 - 26950. [Abstract] [Full Text] [PDF] |
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C. Come, F. Magnino, F. Bibeau, P. De Santa Barbara, K. F. Becker, C. Theillet, and P. Savagner Snail and Slug Play Distinct Roles during Breast Carcinoma Progression. Clin. Cancer Res., September 15, 2006; 12(18): 5395 - 5402. [Abstract] [Full Text] [PDF] |
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F. E. Turner, S. Broad, F. L. Khanim, A. Jeanes, S. Talma, S. Hughes, C. Tselepis, and N. A. Hotchin Slug Regulates Integrin Expression and Cell Proliferation in Human Epidermal Keratinocytes J. Biol. Chem., July 28, 2006; 281(30): 21321 - 21331. [Abstract] [Full Text] [PDF] |
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T. Saito, M. Nagai, and M. Ladanyi SYT-SSX1 and SYT-SSX2 Interfere with Repression of E-Cadherin by Snail and Slug: A Potential Mechanism for Aberrant Mesenchymal to Epithelial Transition in Human Synovial Sarcoma. Cancer Res., July 15, 2006; 66(14): 6919 - 6927. [Abstract] [Full Text] [PDF] |
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T. Toyama, Z. Zhang, H. Iwase, H. Yamashita, Y. Ando, M. Hamaguchi, M. Mizutani, N. Kondo, T. Fujita, Y. Fujii, et al. Low Expression of the Snail Gene is a Good Prognostic Factor in Node-Negative Invasive Ductal Carcinomas Jpn. J. Clin. Oncol., June 1, 2006; 36(6): 357 - 363. [Abstract] [Full Text] [PDF] |
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M. A. Battle, G. Konopka, F. Parviz, A. L. Gaggl, C. Yang, F. M. Sladek, and S. A. Duncan Hepatocyte nuclear factor 4{alpha} orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver PNAS, May 30, 2006; 103(22): 8419 - 8424. [Abstract] [Full Text] [PDF] |
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J. Yang, S. A. Mani, and R. A. Weinberg Exploring a New Twist on Tumor Metastasis. Cancer Res., May 1, 2006; 66(9): 4549 - 4552. [Abstract] [Full Text] [PDF] |
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M. D. Onken, J. P. Ehlers, L. A. Worley, J. Makita, Y. Yokota, and J. W. Harbour Functional Gene Expression Analysis Uncovers Phenotypic Switch in Aggressive Uveal Melanomas. Cancer Res., May 1, 2006; 66(9): 4602 - 4609. [Abstract] [Full Text] [PDF] |
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B. Krishnamachary, D. Zagzag, H. Nagasawa, K. Rainey, H. Okuyama, J. H. Baek, and G. L. Semenza Hypoxia-Inducible Factor-1-Dependent Repression of E-cadherin in von Hippel-Lindau Tumor Suppressor-Null Renal Cell Carcinoma Mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res., March 1, 2006; 66(5): 2725 - 2731. [Abstract] [Full Text] [PDF] |
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H. Yoshida, R. Broaddus, W. Cheng, S. Xie, and H. Naora Deregulation of the HOXA10 Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition Cancer Res., January 15, 2006; 66(2): 889 - 897. [Abstract] [Full Text] [PDF] |
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P. A. Perez-Mancera, M. Perez-Caro, I. Gonzalez-Herrero, T. Flores, A. Orfao, A. G. de Herreros, A. Gutierrez-Adan, B. Pintado, A. Sagrera, M. Sanchez-Martin, et al. Cancer development induced by graded expression of Snail in mice Hum. Mol. Genet., November 15, 2005; 14(22): 3449 - 3461. [Abstract] [Full Text] [PDF] |
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J.-Y. Shih, M.-F. Tsai, T.-H. Chang, Y.-L. Chang, A. Yuan, C.-J. Yu, S.-B. Lin, G.-Y. Liou, M.-L. Lee, J. J.W. Chen, et al. Transcription Repressor Slug Promotes Carcinoma Invasion and Predicts Outcome of Patients with Lung Adenocarcinoma Clin. Cancer Res., November 15, 2005; 11(22): 8070 - 8078. [Abstract] [Full Text] [PDF] |
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J. Long, D. Zuo, and M. Park Pc2-mediated Sumoylation of Smad-interacting Protein 1 Attenuates Transcriptional Repression of E-cadherin J. Biol. Chem., October 21, 2005; 280(42): 35477 - 35489. [Abstract] [Full Text] [PDF] |
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L. Strizzi, C. Bianco, A. Raafat, W. Abdallah, C. Chang, D. Raafat, M. Hirota, S. Hamada, Y. Sun, N. Normanno, et al. Netrin-1 regulates invasion and migration of mouse mammary epithelial cells overexpressing Cripto-1 in vitro and in vivo J. Cell Sci., October 15, 2005; 118(20): 4633 - 4643. [Abstract] [Full Text] [PDF] |
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A. M. Melnick, K. Adelson, and J. D. Licht The Theoretical Basis of Transcriptional Therapy of Cancer: Can It Be Put Into Practice? J. Clin. Oncol., June 10, 2005; 23(17): 3957 - 3970. [Abstract] [Full Text] [PDF] |
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M. Harigopal, A. J. Berger, R. L. Camp, D. L. Rimm, and H. M. Kluger Automated Quantitative Analysis of E-Cadherin Expression in Lymph Node Metastases Is Predictive of Survival in Invasive Ductal Breast Cancer Clin. Cancer Res., June 1, 2005; 11(11): 4083 - 4089. [Abstract] [Full Text] [PDF] |
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H. Yamasaki, T. Sekimoto, T. Ohkubo, T. Douchi, Y. Nagata, M. Ozawa, and Y. Yoneda Zinc finger domain of Snail functions as a nuclear localization signal for importin {beta}-mediated nuclear import pathway Genes Cells, May 1, 2005; 10(5): 455 - 464. [Abstract] [Full Text] [PDF] |
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M. K. Tripathi, S. Misra, S. V. Khedkar, N. Hamilton, C. Irvin-Wilson, C. Sharan, L. Sealy, and G. Chaudhuri Regulation of BRCA2 Gene Expression by the SLUG Repressor Protein in Human Breast Cells J. Biol. Chem., April 29, 2005; 280(17): 17163 - 17171. [Abstract] [Full Text] [PDF] |
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J. I. Yook, X.-Y. Li, I. Ota, E. R. Fearon, and S. J. Weiss Wnt-dependent Regulation of the E-cadherin Repressor Snail J. Biol. Chem., March 25, 2005; 280(12): 11740 - 11748. [Abstract] [Full Text] [PDF] |
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M. Maeda, K. R. Johnson, and M. J. Wheelock Cadherin switching: essential for behavioral but not morphological changes during an epithelium-to-mesenchyme transition J. Cell Sci., March 1, 2005; 118(5): 873 - 887. [Abstract] [Full Text] [PDF] |
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Y. Uchikado, S. Natsugoe, H. Okumura, T. Setoyama, M. Matsumoto, S. Ishigami, and T. Aikou Slug Expression in the E-cadherin Preserved Tumors Is Related to Prognosis in Patients with Esophageal Squamous Cell Carcinoma Clin. Cancer Res., February 1, 2005; 11(3): 1174 - 1180. [Abstract] [Full Text] [PDF] |
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A. Catalano, S. Rodilossi, M. R. Rippo, P. Caprari, and A. Procopio Induction of Stem Cell Factor/c-Kit/Slug Signal Transduction in Multidrug-resistant Malignant Mesothelioma Cells J. Biol. Chem., November 5, 2004; 279(45): 46706 - 46714. [Abstract] [Full Text] [PDF] |
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M. Kajita, K. N. McClinic, and P. A. Wade Aberrant Expression of the Transcription Factors Snail and Slug Alters the Response to Genotoxic Stress Mol. Cell. Biol., September 1, 2004; 24(17): 7559 - 7566. [Abstract] [Full Text] [PDF] |
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C. Bardella, B. Costa, P. Maggiora, S. Patane', M. Olivero, G. N. Ranzani, M. De Bortoli, P. M. Comoglio, and M. F. Di Renzo Truncated RON Tyrosine Kinase Drives Tumor Cell Progression and Abrogates Cell-Cell Adhesion Through E-Cadherin Transcriptional Repression Cancer Res., August 1, 2004; 64(15): 5154 - 5161. [Abstract] [Full Text] [PDF] |
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A. E. Parent, C. Choi, K. Caudy, T. Gridley, and D. F. Kusewitt The Developmental Transcription Factor Slug Is Widely Expressed in Tissues of Adult Mice J. Histochem. Cytochem., July 1, 2004; 52(7): 959 - 965. [Abstract] [Full Text] [PDF] |
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H. Peinado, F. Marin, E. Cubillo, H.-J. Stark, N. Fusenig, M. A. Nieto, and A. Cano Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo J. Cell Sci., June 1, 2004; 117(13): 2827 - 2839. [Abstract] [Full Text] [PDF] |
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C. E. Espineda, J. H. Chang, J. Twiss, S. A. Rajasekaran, and A. K. Rajasekaran Repression of Na,K-ATPase {beta}1-Subunit by the Transcription Factor Snail in Carcinoma Mol. Biol. Cell, March 1, 2004; 15(3): 1364 - 1373. [Abstract] [Full Text] [PDF] |
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H. Peinado, E. Ballestar, M. Esteller, and A. Cano Snail Mediates E-Cadherin Repression by the Recruitment of the Sin3A/Histone Deacetylase 1 (HDAC1)/HDAC2 Complex Mol. Cell. Biol., January 1, 2004; 24(1): 306 - 319. [Abstract] [Full Text] [PDF] |
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M. A. Ginos, G. P. Page, B. S. Michalowicz, K. J. Patel, S. E. Volker, S. E. Pambuccian, F. G. Ondrey, G. L. Adams, and P. M. Gaffney Identification of a Gene Expression Signature Associated with Recurrent Disease in Squamous Cell Carcinoma of the Head and Neck Cancer Res., January 1, 2004; 64(1): 55 - 63. [Abstract] [Full Text] [PDF] |
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F. Tian, S. DaCosta Byfield, W. T. Parks, S. Yoo, A. Felici, B. Tang, E. Piek, L. M. Wakefield, and A. B. Roberts Reduction in Smad2/3 Signaling Enhances Tumorigenesis but Suppresses Metastasis of Breast Cancer Cell Lines Cancer Res., December 1, 2003; 63(23): 8284 - 8292. [Abstract] [Full Text] [PDF] |
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M. Kremer, L. Quintanilla-Martinez, M. Fuchs, A. Gamboa-Dominguez, S. Haye, H. Kalthoff, E. Rosivatz, C. Hermannstadter, R. Busch, H. Hofler, et al. Influence of tumor-associated E-cadherin mutations on tumorigenicity and metastasis Carcinogenesis, December 1, 2003; 24(12): 1879 - 1886. [Abstract] [Full Text] [PDF] |
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M. Conacci-Sorrell, I. Simcha, T. Ben-Yedidia, J. Blechman, P. Savagner, and A. Ben-Ze'ev Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of {beta}-catenin signaling, Slug, and MAPK J. Cell Biol., November 24, 2003; 163(4): 847 - 857. [Abstract] [Full Text] [PDF] |
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T. Hinoi, M. Loda, and E. R. Fearon Silencing of CDX2 Expression in Colon Cancer via a Dominant Repression Pathway J. Biol. Chem., November 7, 2003; 278(45): 44608 - 44616. [Abstract] [Full Text] [PDF] |
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F. Zhang, C. C. Tom, M. C. Kugler, T.-T. Ching, J. A. Kreidberg, Y. Wei, and H. A. Chapman Distinct ligand binding sites in integrin {alpha}3{beta}1 regulate matrix adhesion and cell-cell contact J. Cell Biol., October 13, 2003; 163(1): 177 - 188. [Abstract] [Full Text] [PDF] |
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T. Ohira, R. M. Gemmill, K. Ferguson, S. Kusy, J. Roche, E. Brambilla, C. Zeng, A. Baron, L. Bemis, P. Erickson, et al. WNT7a induces E-cadherin in lung cancer cells PNAS, September 2, 2003; 100(18): 10429 - 10434. [Abstract] [Full Text] [PDF] |
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D. Dominguez, B. Montserrat-Sentis, A. Virgos-Soler, S. Guaita, J. Grueso, M. Porta, I. Puig, J. Baulida, C. Franci, and A. Garcia de Herreros Phosphorylation Regulates the Subcellular Location and Activity of the Snail Transcriptional Repressor Mol. Cell. Biol., July 15, 2003; 23(14): 5078 - 5089. [Abstract] [Full Text] [PDF] |
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K. Sugimachi, S. Tanaka, T. Kameyama, K.-i. Taguchi, S.-i. Aishima, M. Shimada, K. Sugimachi, and M. Tsuneyoshi Transcriptional Repressor Snail and Progression of Human Hepatocellular Carcinoma Clin. Cancer Res., July 1, 2003; 9(7): 2657 - 2664. [Abstract] [Full Text] [PDF] |
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H. Peinado, M. Quintanilla, and A. Cano Transforming Growth Factor {beta}-1 Induces Snail Transcription Factor in Epithelial Cell Lines: MECHANISMS FOR EPITHELIAL MESENCHYMAL TRANSITIONS J. Biol. Chem., May 30, 2003; 278(23): 21113 - 21123. [Abstract] [Full Text] [PDF] |
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V. Bolos, H. Peinado, M. A. Perez-Moreno, M. F. Fraga, M. Esteller, and A. Cano The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors J. Cell Sci., February 1, 2003; 116(3): 499 - 511. [Abstract] [Full Text] [PDF] |
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J. Rios-Doria, K. C. Day, R. Kuefer, M. G. Rashid, A. M. Chinnaiyan, M. A. Rubin, and M. L. Day The Role of Calpain in the Proteolytic Cleavage of E-cadherin in Prostate and Mammary Epithelial Cells J. Biol. Chem., January 3, 2003; 278(2): 1372 - 1379. [Abstract] [Full Text] [PDF] |
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A. Locascio, S. Vega, C. A. de Frutos, M. Manzanares, and M. A. Nieto Biological Potential of a Functional Human SNAIL Retrogene J. Biol. Chem., October 4, 2002; 277(41): 38803 - 38809. [Abstract] [Full Text] [PDF] |
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K. M. Providence, L. A. White, J. Tang, J. Gonclaves, L. Staiano-Coico, and P. J. Higgins Epithelial monolayer wounding stimulates binding of USF-1 to an E-box motif in the plasminogen activator inhibitor type 1 gene J. Cell Sci., January 10, 2002; 115(19): 3767 - 3777. [Abstract] [Full Text] [PDF] |
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