Function of the zinc-finger transcription factor SNAI2 in cancer and development.

Elucidation of the molecular mechanisms that underlie disease development is still a tremendous challenge for basic science, and a prerequisite to the development of new and disease-specific targeted therapies. This review focuses on the function of SNAI2, a member of the Snail family of zinc-finger transcription factors, and discusses its possible role in disease development. SNAI2 has been implicated in diseases of melanocyte development and cancer in humans. Many malignancies arise from a rare population of cells that alone have the ability to self-renew and sustain the tumor (i.e., cancer stem cells). SNAI2 controls key aspects of stem cell function in mouse and human, suggesting that similar mechanisms control normal development and cancer stem cell properties. These insights are expected to contribute significantly to the genetics of cancer and to the development of both cancer therapy and new methods for assessing treatment efficacy.

[1]  M. Clarke,et al.  SLUGging away at cell death. , 2002, Cancer cell.

[2]  D. Metcalf,et al.  The Molecular Control of Hematopoiesis: Progress and Problems with Gene Manipulation , 1998, Stem cells.

[3]  P. A. Pérez-Mancera,et al.  Cancer development induced by graded expression of Snail in mice. , 2005, Human molecular genetics.

[4]  E. Jabs,et al.  Human SLUG gene organization, expression, and chromosome map location on 8q. , 1998, Genomics.

[5]  Andrew P. Read,et al.  Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene , 1994, Nature Genetics.

[6]  D S Latchman,et al.  Transcription-factor mutations and disease. , 1996, The New England journal of medicine.

[7]  Manuel J. Aybar,et al.  Snail precedes Slug in the genetic cascade required for the specification and migration of the Xenopus neural crest , 2003, Development.

[8]  G. Semenza.  Transcriptional regulation of gene expression: Mechanisms and pathophysiology , 1994, Human mutation.

[9]  M. Bronner‐Fraser,et al.  Neural crest induction in Xenopus: evidence for a two-signal model. , 1998, Development.

[10]  M. Bennett,et al.  Cloning and developmental expression of Sna, a murine homologue of the Drosophila snail gene. , 1992, Development.

[11]  A. G. Herreros,et al.  The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells , 2000, Nature Cell Biology.

[12]  P. Wade,et al.  Aberrant Expression of the Transcription Factors Snail and Slug Alters the Response to Genotoxic Stress , 2004, Molecular and Cellular Biology.

[13]  J. Massagué,et al.  Epithelial-Mesenchymal Transitions Twist in Development and Metastasis , 2004, Cell.

[14]  P. Leder,et al.  The hematopoietic growth factor KL is encoded by the SI locus and is the ligand of the c-kit receptor, the gene product of the W locus , 1990, Cell.

[15]  G. Moreno-Bueno,et al.  Correlation of Snail expression with histological grade and lymph node status in breast carcinomas , 2002, Oncogene.

[16]  R. Coffey,et al.  E-cadherin is regulated by the transcriptional repressor SLUG during Ras-mediated transformation of intestinal epithelial cells. , 2005, Surgery.

[17]  R. Balling,et al.  Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene , 1992, Nature.

[18]  E. Fearon,et al.  The SLUG zinc-finger protein represses E-cadherin in breast cancer. , 2002, Cancer research.

[19]  R. Fleischman.  From white spots to stem cells: the role of the Kit receptor in mammalian development. , 1993, Trends in genetics : TIG.

[20]  I. Fabregat,et al.  Snail blocks the cell cycle and confers resistance to cell death. , 2004, Genes & development.

[21]  D G Wilkinson,et al.  Control of cell behavior during vertebrate development by Slug, a zinc finger gene. , 1994, Science.

[22]  M. Murakami,et al.  The Homeoprotein Nanog Is Required for Maintenance of Pluripotency in Mouse Epiblast and ES Cells , 2003, Cell.

[23]  Masataka Nakamura,et al.  Snail regulates p21(WAF/CIP1) expression in cooperation with E2A and Twist. , 2004, Biochemical and biophysical research communications.

[24]  A. Órfão,et al.  Zinc-finger transcription factor Slug contributes to the function of the stem cell factor c-kit signaling pathway. , 2002, Blood.

[25]  K. Zsebo,et al.  Primary structure and functional expression of rat and human stem cell factor DNAs , 1990, Cell.

[26]  E. Ballestar,et al.  Snail Mediates E-Cadherin Repression by the Recruitment of the Sin3A/Histone Deacetylase 1 (HDAC1)/HDAC2 Complex , 2004, Molecular and Cellular Biology.

[27]  M. Nieto,et al.  Regulative response of the cranial neural tube after neural fold ablation: spatiotemporal nature of neural crest regeneration and up-regulation of Slug. , 1995, Development.

[28]  H. Hosokawa,et al.  Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell carcinomas. , 2003, International journal of oncology.

[29]  N. Copeland,et al.  Mast cell growth factor maps near the steel locus on mouse chromosome 10 and is deleted in a number of steel alleles , 1990, Cell.

[30]  David A. Williams,et al.  Stem cell factor is encoded at the SI locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor , 1990, Cell.

[31]  Manuel J. Aybar,et al.  A balance between the anti-apoptotic activity of Slug and the apoptotic activity of msx1 is required for the proper development of the neural crest. , 2004, Developmental biology.

[32]  J. Nesland,et al.  Snail, Slug, and Smad‐interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma , 2005, Cancer.

[33]  J. Toppari,et al.  Stem cell factor functions as a survival factor for mature Leydig cells and a growth factor for precursor Leydig cells after ethylene dimethane sulfonate treatment: implication of a role of the stem cell factor/c-Kit system in Leydig cell development. , 2000, Developmental biology.

[34]  P. A. Pérez-Mancera,et al.  The radioresistance biological function of the SCF/kit signaling pathway is mediated by the zinc-finger transcription factor Slug , 2003, Oncogene.

[35]  A. Look,et al.  SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein. , 1999, Molecular cell.

[36]  L. Sealy,et al.  Regulation of BRCA2 Gene Expression by the SLUG Repressor Protein in Human Breast Cells* , 2005, Journal of Biological Chemistry.

[37]  Y. Ip,et al.  Human Slug Is a Repressor That Localizes to Sites of Active Transcription , 2000, Molecular and Cellular Biology.

[38]  S. Orkin,et al.  Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells , 2004, Nature.

[39]  Eduard Batlle,et al.  Snail Induction of Epithelial to Mesenchymal Transition in Tumor Cells Is Accompanied by MUC1 Repression andZEB1 Expression* , 2002, The Journal of Biological Chemistry.

[40]  J. Thiery.  Epithelial–mesenchymal transitions in tumour progression , 2002, Nature Reviews Cancer.

[41]  G. Chaudhuri,et al.  Negative regulation of the expressions of cytokeratins 8 and 19 by SLUG repressor protein in human breast cells. , 2005, Biochemical and biophysical research communications.

[42]  P. A. Pérez-Mancera,et al.  Mouse cDNA microarray analysis uncovers Slug targets in mouse embryonic fibroblasts. , 2006, Genomics.

[43]  M. Pérez-Caro,et al.  Killing time for cancer stem cells (CSC): discovery and development of selective CSC inhibitors. , 2006, Current medicinal chemistry.

[44]  L. Hudson,et al.  Developmental transcription factor slug is required for effective re‐epithelialization by adult keratinocytes , 2005, Journal of cellular physiology.

[45]  A. Look,et al.  Slug Antagonizes p53-Mediated Apoptosis of Hematopoietic Progenitors by Repressing puma , 2005, Cell.

[46]  Francisco Portillo,et al.  The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression , 2000, Nature Cell Biology.

[47]  M. R. Rippo,et al.  Induction of Stem Cell Factor/c-Kit/Slug Signal Transduction in Multidrug-resistant Malignant Mesothelioma Cells* , 2004, Journal of Biological Chemistry.

[48]  T. Flores,et al.  A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. , 2000, Blood.

[49]  R. Spritz.  Lack of apparent hematologic abnormalities in human patients with c-kit (stem cell factor receptor) gene mutations. , 1992, Blood.

[50]  M. Ozawa,et al.  The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation , 2004, Journal of Cell Science.

[51]  Jean-Philippe Brunet,et al.  The melanocyte differentiation program predisposes to metastasis after neoplastic transformation , 2005, Nature Genetics.

[52]  T. Hunter,et al.  Kit/stem cell factor receptor-induced activation of phosphatidylinositol 3′-kinase is essential for male fertility , 2000, Nature Genetics.

[53]  P. Workman.  Scoring a bull's-eye against cancer genome targets. , 2001, Current opinion in pharmacology.

[54]  M. Nieto,et al.  Conserved and divergent roles for members of the Snail family of transcription factors in the chick and mouse embryo. , 1998, Development.

[55]  S. Nishikawa,et al.  A novel snail-related transcription factor Smuc regulates basic helix-loop-helix transcription factor activities via specific E-box motifs. , 2000, Nucleic acids research.

[56]  Kenneth M. Yamada,et al.  The Zinc-finger Protein Slug Causes Desmosome Dissociation, an Initial and Necessary Step for Growth Factor–induced Epithelial–mesenchymal Transition , 1997 .

[57]  E. Carver,et al.  Slug expression during organogenesis in mice. , 2003, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[58]  R. Spritz,et al.  Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[59]  J. Garcia-conde,et al.  Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. , 2002, Blood.

[60]  D. V. Van Dyke,et al.  Proximal chromosome 8q deletion in a boy with femoral bifurcation and other multiple congenital anomalies , 2004, American journal of medical genetics. Part A.

[61]  Y. Ip,et al.  Snail/slug family of repressors: slowly going into the fast lane of development and cancer. , 2000, Gene.

[62]  Aaron Klug,et al.  In vivo repression by a site-specific DNA-binding protein designed against an oncogenic sequence , 1994, Nature.

[63]  Irving L. Weissman,et al.  Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells , 2003, Nature.

[64]  I. Jackson,et al.  Deficiency of Trp53 rescues the male fertility defects of Kit(W-v) mice but has no effect on the survival of melanocytes and mast cells. , 1999, Developmental biology.

[65]  Nerea Martínez,et al.  The molecular signature of mantle cell lymphoma reveals multiple signals favoring cell survival. , 2003, Cancer research.

[66]  I. Weissman,et al.  A role for Wnt signalling in self-renewal of haematopoietic stem cells , 2003, Nature.

[67]  B. Korf,et al.  Deletion of the SLUG (SNAI2) gene results in human piebaldism , 2003, American journal of medical genetics. Part A.

[68]  J. Nichols,et al.  Functional Expression Cloning of Nanog, a Pluripotency Sustaining Factor in Embryonic Stem Cells , 2003, Cell.

[69]  A. Ferrando,et al.  Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo. , 2002, Cancer cell.

[70]  D. Housman,et al.  The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene , 1988, Cell.

[71]  M. Koch,et al.  Human transcription factor SLUG: mutation analysis in patients with neural tube defects and identification of a missense mutation (D119E) in the Slug subfamily-defining region. , 1999, Mutation research.

[72]  P. A. Pérez-Mancera,et al.  SLUG in cancer development , 2005, Oncogene.

[73]  H. Dressman,et al.  Gene Expression Changes and Signaling Events Associated with the Direct Antimelanoma Effect of IFN-γ , 2005 .

[74]  K. Manova,et al.  Point mutation in Kit receptor tyrosine kinase reveals essential roles for Kit signaling in spermatogenesis and oogenesis without affecting other Kit responses , 2000, The EMBO journal.

[75]  Shoichiro Tsukita,et al.  Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail , 2003, Journal of Cell Science.

[76]  M. Nieto,et al.  The snail superfamily of zinc-finger transcription factors , 2002, Nature Reviews Molecular Cell Biology.

[77]  F. Portillo,et al.  Transcriptional regulation of cadherins during development and carcinogenesis. , 2004, The International journal of developmental biology.

[78]  G. Krystal,et al.  Coexpression of the c-kit and stem cell factor genes in breast carcinomas. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[79]  Michael L. Bittner,et al.  cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene. , 1999 .

[80]  Juan F. García,et al.  Mycosis fungoides shows concurrent deregulation of multiple genes involved in the TNF signaling pathway: an expression profile study. , 2003, Blood.

[81]  F. Bibeau,et al.  Roles of the Transcription Factors Snail and Slug During Mammary Morphogenesis and Breast Carcinoma Progression , 2004, Journal of Mammary Gland Biology and Neoplasia.

[82]  V. Chapman,et al.  The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus , 1988, Nature.

[83]  K. Wikenheiser-Brokamp.  Rb family proteins differentially regulate distinct cell lineages during epithelial development , 2004, Development.

[84]  D. Metcalf,et al.  The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells , 1989, Nature.

[85]  M. Fraga,et al.  The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors , 2003, Journal of Cell Science.

[86]  A. Read,et al.  SLUG (SNAI2) deletions in patients with Waardenburg disease. , 2002, Human molecular genetics.

[87]  C. Yue,et al.  Mechanisms of inactivation of E-cadherin in breast carcinoma: modification of the two-hit hypothesis of tumor suppressor gene , 2001, Oncogene.

[88]  J. Sundberg,et al.  The Slug gene is not essential for mesoderm or neural crest development in mice. , 1998, Developmental biology.

[89]  P. A. Pérez-Mancera,et al.  SLUG (SNAI2) overexpression in embryonic development , 2006, Cytogenetic and Genome Research.

[90]  V. Broudy,et al.  Stem cell factor and hematopoiesis. , 1997, Blood.

[91]  M. Nieto,et al.  Overexpression of Snail family members highlights their ability to promote chick neural crest formation. , 2002, Development.

[92]  Avri Ben-Ze'ev,et al.  Autoregulation of E-cadherin expression by cadherin–cadherin interactions , 2003, The Journal of cell biology.

[93]  C. March,et al.  Identification of a ligand for the c-kit proto-oncogene , 1990, Cell.

[94]  S. Natsugoe,et al.  Slug Expression in the E-cadherin preserved tumors is related to prognosis in patients with esophageal squamous cell carcinoma. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[95]  M. Nieto,et al.  The Snail genes as inducers of cell movement and survival: implications in development and cancer , 2005, Development.

[96]  E. Jabs,et al.  Genomic organization, expression, and chromosome location of the human SNAIL gene (SNAI1) and a related processed pseudogene (SNAI1P). , 1999, Genomics.