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Molecular and Cellular Biology, September 2003, p. 6631-6645, Vol. 23, No. 18
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.18.6631-6645.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Molecular Mechanisms Associated with the Regulation of Apoptosis by the Two Alternatively Spliced Products of c-Myb

Fels Institute for Cancer Research and Molecular Biology,¹ MD/Ph.D. Program, Temple University School of Medicine, Philadelphia, Pennsylvania 19140,² Department of Medicine, Montefiore Medical Center, Bronx, New York 10467³

Received 23 May 2002/ Returned for modification 22 July 2002/ Accepted 17 June 2003

The c-myb proto-oncogene encodes two alternatively spliced mRNAs, which in turn code for proteins of 75 kDa and 89 kDa. It is at present unclear whether the two isoforms of c-Myb perform identical functions or whether they mediate different biological effects. To assess their role in apoptotic death of hematopoietic cells, we expressed the two isoforms of c-Myb in the murine myeloid cell lines 32Dcl3 and FDCP1. Our results show that while ectopic overexpression of p75 c-Myb results in the acceleration of cell death, similar overexpression of p89 c-Myb results in the protection of cells from apoptotic death. An analysis of gene expression changes with mouse cDNA expression arrays revealed that while p75 c-Myb blocked the expression of glutathione S-transferase µ mRNA, p89 c-Myb greatly enhanced the expression of this gene. These results were further confirmed by Northern blot analysis. Ectopic overexpression of the glutathione S-transferase µ gene in 32Dcl3 cells resulted in protection of cells from interleukin-3 withdrawal-induced cell death similar to that seen with the ectopic overexpression of p89 c-Myb. These results suggest that the two isoforms of c-Myb differentially regulate apoptotic death of myeloid cells through differential regulation of glutathione S-transferase µ gene expression.

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