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,
Laboratories of
* Receptor Biology and Gene Expression and
Pathology, Advanced Technology Center, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
Department of Microbiology, Howard University College of Medicine, Washington, D.C. 20059
In this study, we demonstrate that p53 directly inhibits expression
of the T cell growth factor (IL-2) in activated T cells. This
repression is independent of the intrinsic transcriptional activity of
p53 and is mediated by the Tax-responsive
CD28RE-3'-12-O-tetradecanoylphorbol-13-acetate response
element (AP1) element of the IL-2 promoter. Coexpression of the
Tax oncogene causes full reversal of this repression through coordinate
targeting of p300, CREB, and the NF-
B pathways. Paradoxically, IL-2
repression by p53 is not reversed by mdm2. Instead,
mdm2 represses the IL-2 promoter by a mechanism that is
synergistic with p53 and resistant to Tax reversal. The p300
structure-function studies show that these effects are linked to
competitive associations among p53, Tax, and mdm2 with
multiple domains of p300. The functional outcome of these antagonistic
associations is revealed further by the observation that Tax and p53
induce apoptosis in activated T cells through separate and mutually
exclusive pathways. Interestingly, both pathways are abrogated by
mdm2. These results provide evidence that a dynamic
interplay, between Tax and specific elements of the p53 network,
mediates growth factor expression and programmed cell death in
activated T cells.
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