SAM pointed domain ETS factor (SPDEF) regulates terminal differentiation and maturation of intestinal goblet cells

Exp Cell Res. 2010 Feb 1;316(3):452-65. doi: 10.1016/j.yexcr.2009.09.020. Epub 2009 Sep 26.


Background and aims: SPDEF (also termed PDEF or PSE) is an ETS family transcription factor that regulates gene expression in the prostate and goblet cell hyperplasia in the lung. Spdef has been reported to be expressed in the intestine. In this paper, we identify an important role for Spdef in regulating intestinal epithelial cell homeostasis and differentiation.

Methods: SPDEF expression was inhibited in colon cancer cells to determine its ability to control goblet cell gene activation. The effects of transgenic expression of Spdef on intestinal differentiation and homeostasis were determined.

Results: In LS174T colon cancer cells treated with Notch/gamma-secretase inhibitor to activate goblet cell gene expression, shRNAs that inhibited SPDEF also repressed expression of goblet cell genes AGR2, MUC2, RETLNB, and SPINK4. Transgenic expression of Spdef caused the expansion of intestinal goblet cells and corresponding reduction in Paneth, enteroendocrine, and absorptive enterocytes. Spdef inhibited proliferation of intestinal crypt cells without induction of apoptosis. Prolonged expression of the Spdef transgene caused a progressive reduction in the number of crypts that expressed Spdef, consistent with its inhibitory effects on cell proliferation.

Conclusions: Spdef was sufficient to inhibit proliferation of intestinal progenitors and induce differentiation into goblet cells; SPDEF was required for activation of goblet cell associated genes in vitro. These data support a model in which Spdef promotes terminal differentiation into goblet cells of a common goblet/Paneth progenitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Count
  • Cell Differentiation* / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • DNA-Binding Proteins / metabolism
  • Doxycycline / pharmacology
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Goblet Cells / cytology*
  • Goblet Cells / drug effects
  • Goblet Cells / metabolism*
  • Humans
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Intestinal Mucosa / ultrastructure
  • Mice
  • Organ Specificity / drug effects
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-ets / genetics
  • Proto-Oncogene Proteins c-ets / metabolism*
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Transcription Factors / metabolism
  • Transgenes / genetics


  • Atoh1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • Gfi1 protein, mouse
  • Proto-Oncogene Proteins c-ets
  • SPDEF protein, human
  • Spdef protein, mouse
  • Transcription Factors
  • Doxycycline