REGULATORY CASCADES IN GASTROINTESTINAL PROLIFERATION

Summary

Principal Investigator: Hong Fu
Affiliation: University of Pennsylvania
Country: USA
Abstract: Gastrointestinal cancer is a significant health problem, ranking fourth in incidence and second in death in the United States. Abnormal differentiation and increased proliferation are hallmarks of carcinogenesis. The molecular mechanisms that regulate cellular proliferation and differentiation in gastrointestinal development are far from being understood completely. Here we focus on the homeobox-transcription factors Cdx1 and Cdx2, which are primer candidates as central regulators of both intestinal development and GI carcinogenesis. While several hundred articles have appeared that suggest these genes as master regulators of early gut development and GI cancers, the definitive experiment, that is the analysis intestinal epithelia deficient for Cdx1, Cdx2 or both has not yet been performed. Therefore, we will develop and exploit new genetic tools to elucidate fundamental questions regarding the function of these two genes. In addition, in an innovative approach we will use the 1.8 million monoclonal crypts of the mouse intestine as a high- throughput "laboratory" to identify novel proto-oncogenes, tumor suppressors, and cancer modifiers by transposon-mediated insertional mutagenesis. Specific Aims: In Aim 1, we will determine the function of Cdx genes in anterior-posterior patterning of gut endoderm. We will test our hypothesis that Cdx1 and Cdx2 are critical mediators of anterior-posterior patterning of the primitive gut by analyzing the development of early gut endoderm deficient for Cdx1, Cdx2 or Cdx2/Cdx1, which we will obtain by conditional gene ablation in mice. In Aim 2, we will analyze the function of Cdx genes in intestinal differentiation and tumorigenesis. We hypothesize that Cdx1 and Cdx2 are critical regulators of intestinal differentiation, and that Cdx2 acts as a tumor suppressor in the intestinal epithelium. We will evaluate our hypotheses by deriving mice deficient for Cdx1, Cdx2 (or Cdx2/Cdx1) after cytodifferentiation has occurred. Mice will be analyzed for the elaboration of the mature intestinal cell types, for their rate of proliferation, and their propensity for tumorigenesis in multiple models. In Aim 3, we will employ a novel genetic screen to uncover novel proto-oncogenes and tumor suppressors in colorectal cancer. We will utilize the innovative and powerful approach of retrotransposon-driven random insertional mutagenesis to mutagenize the 1.8 million crypts of the mouse intestine. The resulting polyps will be characterized histologically, and the tumor-causing mutation sequenced. Novel proto-oncogenes and tumor suppressor genes will be screen for mutations in human colorectal cancer. Together, this proposal will further our understanding of GI development and cancer, and allow for the development of novel diagnostic and possibly therapeutic tools in the future.
Funding Period: ----------------1998 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. ncbi Foxl1-Cre BAC transgenic mice: a new tool for gene ablation in the gastrointestinal mesenchyme
    Sara D Sackett
    Department of Genetics, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA
    Genesis 45:518-22. 2007
  2. pmc Inhibitor of kappaB kinase beta regulates gastric carcinogenesis via interleukin-1alpha expression
    Kei Sakamoto
    Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
    Gastroenterology 139:226-38.e6. 2010
  3. pmc Transcriptional networks in liver and intestinal development
    Karyn L Sheaffer
    Department of Genetics, Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Cold Spring Harb Perspect Biol 4:a008284. 2012
  4. pmc Krüppel-like factor 4 is involved in functional differentiation of testicular Sertoli cells
    Maren Godmann
    Institute of Anatomy, Developmental Biology, University of Duisburg Essen Medical School, 45122 Essen, Germany
    Dev Biol 315:552-66. 2008
  5. pmc Conditional deletion of Krüppel-like factor 4 delays downregulation of smooth muscle cell differentiation markers but accelerates neointimal formation following vascular injury
    Tadashi Yoshida
    Department of Molecular Physiology and Biological Physics, University of Virginia, 415 Lane Rd, Charlottesville, VA 22908, USA
    Circ Res 102:1548-57. 2008
  6. pmc Epithelial BMP signaling is required for proper specification of epithelial cell lineages and gastric endocrine cells
    Faïza Maloum
    Département d Anatomie et Biologie Cellulaire, Faculte de Medecine et des Sciences de la Sante, Universite de Sherbrooke, Quebec, Canada
    Am J Physiol Gastrointest Liver Physiol 300:G1065-79. 2011
  7. pmc The nuclear pore complex protein Elys is required for genome stability in mouse intestinal epithelial progenitor cells
    Nan Gao
    Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    Gastroenterology 140:1547-55.e10. 2011
  8. pmc Tissue-specific regulation of mouse microRNA genes in endoderm-derived tissues
    Yan Gao
    Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6145, USA
    Nucleic Acids Res 39:454-63. 2011
  9. pmc MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function
    Lindsay B McKenna
    Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19103, USA
    Gastroenterology 139:1654-64, 1664.e1. 2010
  10. pmc Cdx2 regulates endo-lysosomal function and epithelial cell polarity
    Nan Gao
    Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Genes Dev 24:1295-305. 2010

Scientific Experts

  • Sridhar Hannenhalli
  • LINDA GREENBAUM
  • Klaus H Kaestner
  • Nan Gao
  • Lindsay B McKenna
  • Maren Godmann
  • Sara D Sackett
  • Yan Gao
  • Karyn L Sheaffer
  • Faïza Maloum
  • Jonathan Schug
  • Kei Sakamoto
  • Diana Z Ye
  • Blair B Madison
  • Rüdiger Behr
  • Jonathan P Katz
  • Joshua R Friedman
  • Tadashi Yoshida
  • Christoph Seiler
  • Philippe Sarret
  • Yuji Mishina
  • Jean Morisset
  • Kristin Lorent
  • Gangarao Davuluri
  • Joannie M Allaire
  • Jessica Gagné-Sansfaçon
  • Weilong Gong
  • Emma E Furth
  • Evelyne Roy
  • Julie C Carrier
  • Nathalie Perreault
  • Michael Pack
  • Karine Belleville
  • John Le Lay
  • Yoku Hayakawa
  • Keiji Ogura
  • Jaime B McKenna
  • Yoshihiro Hirata
  • Nuria C Bramswig
  • Ayako Yanai
  • Shin Maeda
  • Yohko Hikiba
  • Masao Omata
  • Hayato Nakagawa
  • Anastassios Vourekas
  • Masao Akanuma
  • Andras Nagy
  • Diane Dolson
  • Douglas J Epstein
  • Peter White
  • Karrie Brondell
  • Isabella Gashaw
  • Zhaodong Li
  • Rebecca G Wells
  • Reginald Hurtt
  • Manuela Simoni
  • Florian Guillou
  • Gary K Owens
  • James T Fulmer

Detail Information

Publications17

  1. ncbi Foxl1-Cre BAC transgenic mice: a new tool for gene ablation in the gastrointestinal mesenchyme
    Sara D Sackett
    Department of Genetics, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA
    Genesis 45:518-22. 2007
    ..The Foxl1-Cre line will facilitate the dissection of mesenchymal to epithelial signaling that is known to play a major role in the patterning and function of the gastrointestinal tract...
  2. pmc Inhibitor of kappaB kinase beta regulates gastric carcinogenesis via interleukin-1alpha expression
    Kei Sakamoto
    Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
    Gastroenterology 139:226-38.e6. 2010
    ..Nuclear factor-kappaB (NF-kappaB) is an important transcription factor involved in various biological processes, including carcinogenesis. However, it is unknown whether NF-kappaB activation is involved in gastric carcinogenesis...
  3. pmc Transcriptional networks in liver and intestinal development
    Karyn L Sheaffer
    Department of Genetics, Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Cold Spring Harb Perspect Biol 4:a008284. 2012
    ..Discussion of these transcriptional mechanisms gives us insight into how the primitive gut, composed of simple endodermal cells, develops into multiple diverse cell types that are organized into complex mature organs...
  4. pmc Krüppel-like factor 4 is involved in functional differentiation of testicular Sertoli cells
    Maren Godmann
    Institute of Anatomy, Developmental Biology, University of Duisburg Essen Medical School, 45122 Essen, Germany
    Dev Biol 315:552-66. 2008
    ..In summary, KLF4 plays a significant role for proper and timely Sertoli cell differentiation in pubertal mice...
  5. pmc Conditional deletion of Krüppel-like factor 4 delays downregulation of smooth muscle cell differentiation markers but accelerates neointimal formation following vascular injury
    Tadashi Yoshida
    Department of Molecular Physiology and Biological Physics, University of Virginia, 415 Lane Rd, Charlottesville, VA 22908, USA
    Circ Res 102:1548-57. 2008
    ..Taken together, we have demonstrated that Klf4 plays a critical role in regulating expression of SMC differentiation markers and proliferation of SMCs in vivo in response to vascular injury...
  6. pmc Epithelial BMP signaling is required for proper specification of epithelial cell lineages and gastric endocrine cells
    Faïza Maloum
    Département d Anatomie et Biologie Cellulaire, Faculte de Medecine et des Sciences de la Sante, Universite de Sherbrooke, Quebec, Canada
    Am J Physiol Gastrointest Liver Physiol 300:G1065-79. 2011
    ..Our data also indicate that loss of BMP signaling in epithelial gastric cells alone is not sufficient to induce gastric neoplasia...
  7. pmc The nuclear pore complex protein Elys is required for genome stability in mouse intestinal epithelial progenitor cells
    Nan Gao
    Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    Gastroenterology 140:1547-55.e10. 2011
    ..However, it is not known whether loss of Elys has a similar effect in the mammalian intestine or whether the NPC and DNA repair defects each contribute to the overall phenotype...
  8. pmc Tissue-specific regulation of mouse microRNA genes in endoderm-derived tissues
    Yan Gao
    Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6145, USA
    Nucleic Acids Res 39:454-63. 2011
    ..We determined that the same transcriptional regulatory mechanisms govern tissue-specific gene expression of both mRNA and microRNA encoding genes in mammals...
  9. pmc MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function
    Lindsay B McKenna
    Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19103, USA
    Gastroenterology 139:1654-64, 1664.e1. 2010
    ..We aimed to quantify the complete miRNA expression profile of the mammalian intestinal mucosa and to determine the contribution of miRNAs to intestinal homeostasis using genetic means...
  10. pmc Cdx2 regulates endo-lysosomal function and epithelial cell polarity
    Nan Gao
    Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Genes Dev 24:1295-305. 2010
    ..These results demonstrate that Cdx2 regulates epithelial cell polarity and morphogenesis through control of apical protein transport and endo-lysosomal function...
  11. pmc FoxF1 and FoxL1 link hedgehog signaling and the control of epithelial proliferation in the developing stomach and intestine
    Blair B Madison
    Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 284:5936-44. 2009
    ..Furthermore, expression of both Foxf1 and Foxl1 is reduced in the Gli2/Gli3 mutant gut. These results provide compelling evidence that Foxf1 and Foxl1 are mediators of the Hh (endoderm) to mesoderm signaling pathway...
  12. pmc Krüppel-like factor 4, a "pluripotency transcription factor" highly expressed in male postmeiotic germ cells, is dispensable for spermatogenesis in the mouse
    Maren Godmann
    Institute of Anatomy, Developmental Biology, Hufelandstrasse 55, University of Duisburg Essen Medical School, 45122 Essen, Germany
    Mech Dev 126:650-64. 2009
    ..However, in summary, the lack of KLF4 alone does not prevent complete spermatogenesis...
  13. pmc Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2
    Nan Gao
    Department of Genetics, and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA
    Dev Cell 16:588-99. 2009
    ..We conclude that Cdx2 controls important aspects of intestinal identity and development, and that this function is largely independent of the enteric Hox code...
  14. pmc The evolution of Fox genes and their role in development and disease
    Sridhar Hannenhalli
    Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Nat Rev Genet 10:233-40. 2009
    ..We summarize the salient features of the evolution of the Fox gene family and highlight the diverse contribution of various Fox subfamilies to developmental processes, from organogenesis to speech acquisition...
  15. pmc Foxl1 is a marker of bipotential hepatic progenitor cells in mice
    Sara D Sackett
    Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Hepatology 49:920-9. 2009
    ..These results demonstrate that the early Foxl1-Cre lineage cell gives rise to both cholangiocytes and hepatocytes after liver injury and suggest the potential for progenitor-portal fibroblast cell interactions...
  16. pmc Foxa1 and Foxa2 control the differentiation of goblet and enteroendocrine L- and D-cells in mice
    Diana Z Ye
    Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Gastroenterology 137:2052-62. 2009
    ..These findings suggest Foxa1/a2 as critical factors in the differentiation of gut epithelial cells...