Evidence for NF-κB- and CBP-Independent Repression of p53's Transcriptional Activity by Human T-Cell Leukemia Virus Type 1 Tax in Mouse Embryo and Primary Human Fibroblasts

Abstract

The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein can repress the transcriptional activity of the tumor suppressor protein p53. However, it remains controversial whether Tax requires NF-B factors/ activity and/or p300/CBP in order to inactivate p53 function. To address this issue, we have investigated Tax

Activation of NF-κB by HTLV-I and implications for cell transformation

“…Since RelA phosphorylation is known to promote its binding to CBP/p300, the NF-kB-dependent p53 inactivation may also involve RelA-mediated sequestration of transcriptional coactivators (Figure 3). It is noteworthy, however, that Tax may also inactivate p53 via an NF-kB-and CBP/p300-independent mechanism (Miyazato et al, 2005). Nevertheless, it seems clear that the Tax-mediated NF-kB activation contributes to p53 inactivation at least under certain conditions.…”

Molecular mechanisms of cellular transformation by HTLV-1 Tax

“…An alternative notion is that Tax acts through an NF-kB/RelA(p65) pathway to perturb p53 function (Pise-Masison et al, 2000a, b). Two recent papers suggest that neither the NF-kB pathway nor the p300/CBP route fully explains Tax's inactivation of p53 (Jeong et al, 2005;Miyazato et al, 2005).…”

Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells

“…The transfection program for ST1 (O-17), HuT102 (O-16), KOB (T-20) and KK1 cells (T-20) was determined so that high levels of transfection efficiency and cell viability could be achieved (data not shown). Cells were transfected with the luciferase reporter plasmid containing 13 copies of a p53 consensus binding site (pG13-Luc) and incubated with or without Nutlin-3a for 24 h. 20 Luciferase activity in 10 mg cell lysate was measured using luciferase assay reagents (Promega) according to the manufacturer's instructions in a TD-20/20 luminometer (Turner Designs, Sunnyvale, CA, USA). Each experiment was carried out in triplicate.…”

“…[17][18][19] To date, several different mechanisms by which Tax inactivates p53 have been proposed, although the effects are indirect and complex. 20,21 Mutations in the p53 gene are found in about 50% of human cancers, and they abrogate DNA binding and the transactivation of p53. 22 Wild-type p53 protein is inactivated through binding to a specific E3 ubiquitin ligase, MDM2, which mediates the degradation of p53.…”