Cross-Regulation of T Cell Growth Factor Expression by p53 and the Tax Oncogene

Abstract

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-κB 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.

The Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax Controls Forkhead Box O4 Activity through Degradation by the Proteasome

“…In this context, fluctuations in the expression of Tax during infection might contribute to the repression or activation of FoxO4 activity and therefore to cell proliferation or cell cycle arrest and apoptosis. Consistent with this hypothesis, FoxO4 inactivation is associated with proliferation and survival of T cells (10), and Tax-induced apoptosis in activated T cells is abrogated by MDM2 (13).…”

Kinetic profiles of p300 occupancy in vivo predict common features of promoter structure and coactivator recruitment

“…All transfections were carried out in triplicate, and the data shown represent at least three independent experiments. The IL2, p21͞WAF1͞CDKN1A, and GADD153͞ DDIT3 luciferase promoter reporter plasmids have been described (11)(12)(13). The p16͞CDKN2A promoter luciferase reporter plasmid was generated by PCR amplification of a 505-bp fragment of p16͞CDKN2A with p16F 5Ј-CCAAACAC-CCCGATTCAATTTGGCA-3Ј and p16RC 5Ј-CCGCTGC-CTGCTCTACCCCTCTCC-3Ј primers.…”

“…Cells were sonicated with three 15-s pulses with a Sonic Dismembrator (Fisher Scientific) set at 50% of the maximum output, disrupting 95% of the cells. Chromatin was immunoprecipitated from 500 g of soluble chromatin from each time point by using affinity-purified anti-p300 polyclonal antibody (11). Immunoprecipitated protein-DNA complexes were washed seven times with radioimmunoprecipitation assay buffer (1% Nonidet P-40͞0.5% deoxycholate in PBS), twice with high-salt radioimmunoprecipitation assay buffer (500 mM NaCl͞1% Nonidet P-40͞0.5% deoxycholate in PBS), and twice with TE (10 mM Tris, pH 8.0͞1 mM EDTA).…”

Novel Cell-specific and Dominant Negative Anti-apoptotic Roles of p73 in Transformed Leukemia Cells

“…The recently described role of the p53 family member, p73, in T-cell receptor-activated induced cell death emphasizes its critical role in T-cell immune function (1). The well established role of tumor suppressor p53 in apoptosis correlates with the high prevalence of p53 gene mutations in 30% of adult T-cell lymphomas (2)(3)(4)(5). Unlike p53, numerous studies have failed to demonstrate p73 tumor-associated mutations (6 -13).…”