Tcf binding sequence and position determines β‐catenin and Lef‐1 responsiveness of MMP‐7 promoters

The matrix metalloproteinase‐7 (MMP‐7) gene is a target of β‐catenin transactivation. Expression of the T‐cell factor, Lef‐1, enhances transcriptional activation of the human MMP‐7 promoter by β‐catenin, but represses activation of the mouse MMP‐7 promoter, both activities through consensus Tcf binding sites. The mouse promoter has a single Tcf binding element (mTBE) located downstream of the transcriptional start site, while the human promoter has two Tcf binding elements (hTBE1, hTBE2), both located upstream of the transcriptional start. hTBE1 and hTBE2 also differ in sequence from mTBE. Here we demonstrate that positioning of mTBE, upstream or downstream of the transcriptional start site dictated whether Lef‐1 functioned as an activator or repressor, respectively. Sequence differences between mTBE and hTBE sites determined the potency of these activities, with hTBE sites being weaker. Mutational analysis of mTBE showed that increased Lef‐1 activity mapped to G · C base pairings at 5′ and 3′ ends, and correlated with a threefold increase in Lef‐1 binding affinity in vitro. Heterologous promoters with high affinity binding sites were 115‐fold more responsive to β‐catenin than those with low affinity sites. Converting low affinity Tcf binding sites to high affinity sites increased β‐catenin responsiveness of the mouse and human promoters by 2–3 fold, and ectopic expression of Lef‐1 increased β‐catenin responsiveness for promoters with low affinity binding sequences. We concluded that sequence and position of Tcf binding sites can determine the extent of β‐catenin‐Lef‐1 responsiveness for β‐catenin target genes. © 2004 Wiley‐Liss, Inc.

[1]  Karine Hovanes,et al.  β-catenin–sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer , 2001, Nature Genetics.

[2]  Paul Polakis,et al.  The metalloproteinase matrilysin is a target of β-catenin transactivation in intestinal tumors , 1999, Oncogene.

[3]  E. Lander,et al.  Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse , 1993, Cell.

[4]  H. Aberle,et al.  Cadherin‐catenin complex: Protein interactions and their implications for cadherin function , 1996, Journal of cellular biochemistry.

[5]  Thomas Kirchner,et al.  β-Catenin Regulates the Expression of the Matrix Metalloproteinase-7 in Human Colorectal Cancer , 1999 .

[6]  F. McCormick,et al.  Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. , 1999, Nature.

[7]  K. Takishima,et al.  Interaction of NF‐Y with the 3′‐flanking DNA sequence of the CCAAT box , 2003, FEBS letters.

[8]  K. Kinzler,et al.  Lessons from Hereditary Colorectal Cancer , 1996, Cell.

[9]  Kathleen R. Cho,et al.  Novel candidate targets of beta-catenin/T-cell factor signaling identified by gene expression profiling of ovarian endometrioid adenocarcinomas. , 2003, Cancer research.

[10]  Bert Vogelstein,et al.  Mutational Analysis of the APC/β-Catenin/Tcf Pathway in Colorectal Cancer , 1998 .

[11]  M. Buendia,et al.  Transcriptional Activation of Interleukin-8 by β-Catenin-Tcf4* , 2002, The Journal of Biological Chemistry.

[12]  M. Buendia,et al.  Transcriptional activation of interleukin-8 by beta-catenin-Tcf4. , 2002, The Journal of biological chemistry.

[13]  H Clevers,et al.  Sequence-specific high mobility group box factors recognize 10-12-base pair minor groove motifs. , 2000, The Journal of biological chemistry.

[14]  T. Ishikawa,et al.  Matrilysin gene expression in sporadic and familial colorectal adenomas , 1997, Molecular carcinogenesis.

[15]  A. Liberzon,et al.  Role of intrinsic DNA binding specificity in defining target genes of the mammalian transcription factor PDX1. , 2004, Nucleic acids research.

[16]  P. Polakis,et al.  Deletion of an amino-terminal sequence beta-catenin in vivo and promotes hyperphosporylation of the adenomatous polyposis coli tumor suppressor protein , 1996, Molecular and cellular biology.

[17]  B. Fingleton,et al.  The PEA3 Subfamily of Ets Transcription Factors Synergizes with β-Catenin–LEF-1 To Activate Matrilysin Transcription in Intestinal Tumors , 2001, Molecular and Cellular Biology.

[18]  R Grosschedl,et al.  Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions. , 1995, Genes & development.

[19]  B. Herrmann,et al.  Nuclear localization of β-catenin by interaction with transcription factor LEF-1 , 1996, Mechanisms of Development.

[20]  K. Sikora,et al.  c‐myc oncogene expression in colorectal cancer , 1987, Cancer.

[21]  Hiroyuki Yamamoto,et al.  Association of ets‐related transcriptional factor E1AF expression with tumour progression and overexpression of MMP‐1 and matrilysin in human colorectal cancer , 2003, The Journal of pathology.

[22]  Michael Kühl,et al.  Functional interaction of β-catenin with the transcription factor LEF-1 , 1996, Nature.

[23]  B. Gumbiner,et al.  Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of β-catenin , 1998, Current Biology.

[24]  J. Horowitz,et al.  Sp2 DNA Binding Activity and trans-Activation Are Negatively Regulated in Mammalian Cells* , 2004, Journal of Biological Chemistry.

[25]  B. Hogan,et al.  Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[26]  R Grosschedl,et al.  DNA-binding properties of the HMG domain of the lymphoid-specific transcriptional regulator LEF-1. , 1991, Genes & development.

[27]  C. Klinge,et al.  Estrogen receptor beta isoforms exhibit differences in ligand-activated transcriptional activity in an estrogen response element sequence-dependent manner. , 2004, Endocrinology.

[28]  A. Moser,et al.  Loss of Apc+ in intestinal adenomas from Min mice. , 1994, Cancer research.

[29]  K. Umesono,et al.  Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors , 1991, Cell.

[30]  Karine Hovanes,et al.  A New β-Catenin-dependent Activation Domain in T Cell Factor* 210 , 2003, The Journal of Biological Chemistry.

[31]  S. Ho,et al.  Engineering hybrid genes without the use of restriction enzymes: gene splicing by overlap extension. , 1989, Gene.

[32]  S. Teichmann,et al.  Functional determinants of transcription factors in Escherichia coli: protein families and binding sites. , 2003, Trends in genetics : TIG.

[33]  Kathleen R. Cho,et al.  ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with beta-catenin defects and promotes neoplastic transformation. , 2002, Cancer cell.

[34]  E. Fuchs,et al.  Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate. , 1995, Genes & development.

[35]  O. Destrée,et al.  Lef-1 and Tcf-3 Transcription Factors Mediate Tissue-Specific Wnt Signaling during Xenopus Development , 2002, Current Biology.

[36]  Stephen W. Byers,et al.  Serine Phosphorylation-regulated Ubiquitination and Degradation of β-Catenin* , 1997, The Journal of Biological Chemistry.

[37]  P. Farnham,et al.  Identification of the polycomb group protein SU(Z)12 as a potential molecular target for human cancer therapy. , 2003, Molecular cancer therapeutics.

[38]  Hans Clevers,et al.  The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. , 2002, Cell.

[39]  Karine Hovanes,et al.  A new beta-catenin-dependent activation domain in T cell factor. , 2003, The Journal of biological chemistry.

[40]  R. Knuechel,et al.  Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  S. Byers,et al.  Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin. , 1997, The Journal of biological chemistry.

[42]  C. Albanese,et al.  The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[43]  David A. Case,et al.  Structural basis for DNA bending by the architectural transcription factor LEF-1 , 1995, Nature.

[44]  T. Brabletz,et al.  beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. , 1999, The American journal of pathology.

[45]  T. Minamoto,et al.  Oncogenic beta-catenin and MMP-7 (matrilysin) cosegregate in late-stage clinical colon cancer. , 2002, Gastroenterology.

[46]  Yusuke Nakamura,et al.  Identification of membrane-type matrix metalloproteinase-1 as a target of the β-catenin/Tcf4 complex in human colorectal cancers , 2002, Oncogene.

[47]  H. Hibshoosh,et al.  Increased expression of cyclin D1 is an early event in multistage colorectal carcinogenesis. , 1996, Gastroenterology.

[48]  R Grosschedl,et al.  Functional interaction of beta-catenin with the transcription factor LEF-1. , 1996, Nature.

[49]  Hans Clevers,et al.  Caught up in a Wnt storm: Wnt signaling in cancer. , 2003, Biochimica et biophysica acta.

[50]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[51]  H. Clevers,et al.  Identification and cloning of TCF‐1, a T lymphocyte‐specific transcription factor containing a sequence‐specific HMG box. , 1991, The EMBO journal.

[52]  L. Matrisian,et al.  Structure and expression of the human gene for the matrix metalloproteinase matrilysin. , 1994, The Journal of biological chemistry.

[53]  H Clevers,et al.  Extensive alternative splicing and dual promoter usage generate Tcf-1 protein isoforms with differential transcription control properties , 1996, Molecular and cellular biology.

[54]  Rudolf Grosschedl,et al.  The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures , 1992, Cell.

[55]  H. Goh,et al.  c-myc Oncogene expression in colorectal cancer: its use in prognosis and role in colorectal carcinogenesis. , 1990, Annals of the Academy of Medicine, Singapore.

[56]  L. Matrisian,et al.  The metalloproteinase matrilysin is preferentially expressed by epithelial cells in a tissue-restricted pattern in the mouse. , 1995, Molecular biology of the cell.

[57]  P. Polakis,et al.  Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[58]  B. Henderson.  Nuclear-cytoplasmic shuttling of APC regulates β-catenin subcellular localization and turnover , 2000, Nature Cell Biology.

[59]  A. Sparks,et al.  Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. , 1998, Cancer research.

[60]  H Clevers,et al.  All Tcf HMG box transcription factors interact with Groucho-related co-repressors. , 2001, Nucleic acids research.

[61]  Doris Wedlich,et al.  The Wnt/Wg Signal Transducer β-Catenin Controls Fibronectin Expression , 1999, Molecular and Cellular Biology.

[62]  Andreas Hecht,et al.  Identification of a Promoter-specific Transcriptional Activation Domain at the C Terminus of the Wnt Effector Protein T-cell Factor 4* , 2003, The Journal of Biological Chemistry.

[63]  H. Clevers,et al.  Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1. , 1999, Science.