Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice.
OBJECTIVE
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.
Duckworth
Carrie A
CA
Division of Gastroenterology, University of Liverpool, Liverpool, United Kingdom.
Pritchard
D Mark
DM
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology / Q000528:radiation effects; D003106:Colon / Q000473:pathology* / Q000502:physiology; D003110:Colonic Neoplasms / Q000473:pathology / Q000503:physiopathology; D019858:Enteroendocrine Cells / Q000473:pathology / Q000502:physiology; D005260:Female; D005720:Gamma Rays; D020397:Goblet Cells / Q000473:pathology / Q000502:physiology; D006965:Hyperplasia; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000473:pathology* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008938:Mitosis / Q000502:physiology / Q000528:radiation effects; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics* / Q000378:metabolism
C494773:Bak1 protein, mouse; D050998:bcl-2 Homologous Antagonist-Killer Protein