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Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice.

AbstractBACKGROUND & AIMS:
Members of the bcl-2 family of proteins are important determinants of cell fate. Bcl-2 and bcl-w have previously been identified as antiapoptotic members of this family that promote gastrointestinal epithelial cell survival. However, a proapoptotic family member that exerts important effects in the gastrointestinal tract has not yet been identified. We have therefore investigated intestinal epithelial apoptosis in bak-null mice.
METHODS:
Apoptosis, mitosis, differentiated cell composition, and cell number were assessed on a cell positional basis in the small intestinal and colonic epithelia of bak-null mice and their C57BL/6 wild-type counterparts. Apoptosis was induced by 1-Gy gamma-irradiation or 10mg/kg azoxymethane (AOM). Aberrant crypt foci were induced by 3 weekly injections of 10mg/kg AOM.
RESULTS:
The amount of spontaneous apoptosis in the colonic intercrypt table was reduced, and colonic crypt cell number and mitotic index were elevated in bak-null mice relative to C57BL/6 wild-type mice. Bak-null colonic crypts contained more goblet cells and fewer endocrine cells than those from C57BL/6 mice. Fewer colonic epithelial apoptotic cells were observed after gamma-radiation and AOM in bak-null mice, and these mice also displayed greater numbers of colonic AOM-induced aberrant crypt foci. None of these parameters differed in the small intestinal epithelium of bak-null mice compared with C57BL/6.
CONCLUSIONS:
Bak prevents colonic crypt hyperplasia by regulating spontaneous apoptosis at the colonic intercrypt table region and also regulates damage-induced apoptosis in the colonic crypt. Deletion of bak in vivo results in altered colonic proliferation and differentiation, and causes increased susceptibility to colonic carcinogenesis.
AuthorsCarrie A Duckworth, D Mark Pritchard
JournalGastroenterology (Gastroenterology) Vol. 136 Issue 3 Pg. 943-52 (Mar 2009) ISSN: 1528-0012 [Electronic] United States
PMID19185578 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Bak1 protein, mouse
  • bcl-2 Homologous Antagonist-Killer Protein
Topics
  • Animals
  • Apoptosis (physiology)
  • Cell Count
  • Cell Differentiation (physiology)
  • Cell Division (physiology, radiation effects)
  • Colon (pathology, physiology)
  • Colonic Neoplasms (pathology, physiopathology)
  • Enteroendocrine Cells (pathology, physiology)
  • Female
  • Gamma Rays
  • Goblet Cells (pathology, physiology)
  • Hyperplasia
  • Immunohistochemistry
  • Intestinal Mucosa (pathology, physiology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mitosis (physiology, radiation effects)
  • bcl-2 Homologous Antagonist-Killer Protein (genetics, metabolism)

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