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Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo

Oncogene volume 18, pages 7287–7293 (1999)Cite this article

Abstract

The influence of bcl-2 and bax expression on apoptotic cell death in mouse intestinal epithelia was assessed using homozygously null mice. Apoptosis was induced in vivo by the enterotoxin 5-fluorouracil (5FU) or by γ-irradiation and its cell positional incidence was assessed. 5FU and γ-radiation treated bax-null mice surprisingly showed no reductions in apoptotic yield in the small intestine or midcolon at 4.5 h at cell positions in which both agents had previously been shown to strongly induce p53 protein expression. The colonic epithelia of 5FU treated bcl-2-null mice showed elevated levels of apoptosis at 4.5 h: from 48 apoptotic events in wild-type mice to 273 in the nulls, scoring 200 half crypts. The increase occurred specifically in the cell positions considered to harbour colonic stem cells, at the base of crypts, where there is selective expression of bcl-2. There was a modest but significant increase in apoptosis in the small intestine of the bcl-2-null mice although the epithelia of wild-type mice here are not immunohistochemically positive for bcl-2 protein. These findings show that bcl-2 plays a key role in determining the sensitivity of colonic stem cells to damage-induced death but that bax is not responsible for the p53-dependent induction of apoptosis in this context.

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Acknowledgements

We wish to thank members of the Department of Epithelial Biology at the Paterson Institute for technical assistance and Dr Ann Jackman and Professor Alastair Watson for valuable discussion. We are grateful to Dr Dennis Loh for providing the breeding stock for bcl-2 heterozygous animals. The work was supported by Zeneca Pharmaceuticals, the Digestive Disorders Foundation, the Medical Research Council and the Cancer Research Campaign.

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Authors and Affiliations

  1. CRC Molecular and Cellular Pharmacology Group, School of Biological Sciences, Stopford Building (G38), University of Manchester, Manchester M13 9PT, UK

    D Mark Pritchard & John A Hickman

  2. CRC Department of Epithelial Biology, Paterson Institute, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 9BX, UK

    D Mark Pritchard & Christopher S Potten

  3. Dana-Farber Cancer Institute, 44 Binney Street, Boston, 02115, Massachusetts, MA, USA

    Stanley J Korsmeyer

  4. CRC Biomathematics and Computing Unit, Paterson Institute, Christie Hospital NHS Trust, Wilmslow Road, M20 9BX, Manchester, UK

    Steven Roberts

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Pritchard, D., Potten, C., Korsmeyer, S. et al. Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo. Oncogene 18, 7287–7293 (1999). https://doi.org/10.1038/sj.onc.1203150

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