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Molecular and Cellular Biology, March 2003, p. 1520-1533, Vol. 23, No. 5
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.5.1520-1533.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Mutations in the v-Rel Transactivation Domain Indicate Altered Phosphorylation and Identify a Subset of NF-B-Regulated Cell Death Inhibitors Important for v-Rel Transforming Activity

Béatrice Rayet,^1, Yongjun Fan,¹ and Céline Gélinas^1,2*

Center for Advanced Biotechnology and Medicine,¹ Department of Biochemistry, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5638²

Received 16 July 2002/ Returned for modification 4 September 2002/ Accepted 5 December 2002

Consistent with the constitutive activation of Rel/NF-B in human hematopoietic tumors, the v-Rel oncoprotein induces aggressive leukemia/lymphomas in animal models. v-Rel is thus a valuable tool to characterize the role of Rel/NF-B in cancer and the mechanisms involved. Prior studies by our group identified a serine-rich domain in v-Rel that was required for biological activity. Here, we investigated the molecular basis for the transformation defect of specific serine mutants. We show that the transforming efficiency of these mutants in primary lymphoid cells is correlated with their ability to mediate B site-dependent transactivation and with specific changes in phosphorylation profiles. Interestingly, coexpression of the death antagonists Bcl-xL and Bcl-2 significantly increased their oncogenicity, whereas other NF-B-regulated death inhibitors showed little or no effect. The fact that a subset of apoptosis inhibitors could rescue v-Rel transactivation mutants suggests that their reduced transcriptional activity may critically affect expression of defined death antagonists essential for oncogenesis. Consistent with this hypothesis, we observed selection for high endogenous expression of Bcl-2-related death antagonists in cells transformed by weakly transforming v-Rel mutants. These results emphasize the need for Rel/NF-B to efficiently activate expression of a subset of antiapoptotic genes from the Bcl-2 family to manifest its oncogenic phenotype.

Present address: Laboratoire de Physiologie des Membranes, CNRS UMR6078, Université de Nice-Sophia Antipolis, 06230 Villefranche sur Mer, France.

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