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c-Myb Down-Regulation Is Associated with Human Colon Cell Differentiation, Apoptosis, and Decreased Bcl-2 Expression¹

Ludwig Institute for Cancer Research, P. O. Royal Melbourne Hospital 3050, Melbourne, Victoria, Australia [M. A. T., M. A. R., R. H. W.], and Peter MacCallum Cancer Institute, East Melbourne 3002, Victoria, Australia [S. L. E., A. J. F., M. I. Z., R. G. R.]

c-myb is expressed in human and murine colonic mucosa and elevated expression occurs in premalignant adenomatous polyps and carcinomas. c-Myb is required for colon cell proliferation, and there is evidence of c-myb down-regulation during differentiation. Recently, c-myb has been implicated in hematopoietic cell survival via regulation of bcl-2 gene expression. However, c-myb expression during terminal differentiation and apoptosis in the colonic crypt has not been examined. The experiments in this study examine the spatial and temporal expression of c-Myb protein in vivo using human colonic crypt sections and in vitro in human colon tumor cell lines undergoing butyrate-induced differentiation and apoptosis. Electron microscopy, together with molecular and biochemical analysis, was used to define the differentiation status of the cells. Results demonstrate a decrease in c-Myb expression during the commitment of cells to differentiation and apoptosis. Decreased levels of c-Myb are accompanied by a decrease in Bcl-2. These data suggest that the transcription factor c-Myb has a role in regulating the balance between proliferation, differentiation, and apoptosis in the colonic crypt. Furthermore, elevated c-Myb levels in colon tumor cells may lead to persistent bcl-2 expression, thus protecting tumor cells from programmed cell death.

¹ This work was supported by a grant from the Anti Cancer Council of Victoria, Australia.

² To whom requests for reprints should be addressed, at Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, East Melbourne 8006, Victoria, Australia. Phone: 613-9656-1863; Fax: 613-9656-1411; E-mail: r.ramsay@pmci.unimelb.edu.au.

Received 5/22/98. Accepted 9/14/98.

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