Genetic Evidence of a Role for ATM in Functional Interaction between Human T-Cell Leukemia Virus Type 1 Tax and p53

Abstract

Recent evidence from several investigators suggest that the human T-cell leukemia virus type 1 Tax oncoprotein represses the transcriptional activity of the tumor suppressor protein, p53. An examination of published findings reveals serious controversy as to the mechanism(s) utilized by Tax to inhibit p53 activity and whether the same mechanism is used by Tax in adherent and suspension cells. Here, we have investigated Tax-p53 interaction simultaneously in adherent epithelial (HeLa and Saos) and suspension T-lymphocyte (Jurkat) cells. Our results indicate that Tax activity through the CREB/CREB-binding protein (CBP), but not NF-B, pathway is needed to repress the transcriptional activity of p53 in all tested cell lines. However, we did find that while CBP binding by Tax is necessary, it is not sufficient for inhibiting p53 function. Based on knockout cell studies, we correlated a strong genetic requirement for the ATM, but not protein kinasedependent DNA, protein in conferring a Tax-p53-repressive phenotype.

Molecular mechanisms of cellular transformation by HTLV-1 Tax

“…Curiously, unlike most other cancers, only a small fraction of ATL cells have p53 mutation. This paradox was elegantly resolved by independent findings that p53 function is inactivated by Tax (Reid et al, 1993;Akagi et al, 1997b;Mulloy et al, 1998;Pise-Masison et al, 1998;Ariumi et al, 2000;Van et al, 2001). What remains incompletely answered is how Tax inactivates p53.…”

“…Tax expression frequently engenders multinucleated polyploid cells (Jin et al, 1998;Liang et al, 2002). Additionally, because Tax also inactivates (Akagi et al, 1997a;Neuveut et al, 1998;Pise-Masison et al, 1998;Takemoto et al, 2000;Van et al, 2001), two factors essential to a G1 tetraploid/ polypoid checkpoint (Margolis et al, 2003), it is reasonable that the polyploidy to aneuploidy mechanism can contribute to ATL transformation.…”

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

“…Two major theories have been proposed to explain the inactivation of p53 by Tax. First, it has been proposed that Tax and p53 compete for binding to the ubiquitous coactivator CREB binding protein (CBP)/ p300, thereby decreasing the ability of p53 to activate target gene expression (Suzuki et al, 1999b;Van et al, 2001). Sequestration of these critical cofactors by Tax would decrease the ability of p53 to activate target gene expression (Van Orden and Nyborg, 2000).…”

Cellular Transformation by the HTLV-I Tax Protein, a Jack-of-All-Trades

“…If Tax outcompetes p53 for CBP/p300 binding, p53-mediated transactivation of cellular genes is inhibited (Van Orden et al, 1999a, b;Suzuki et al, 1999b;Ariumi et al, 2000). Recently, Tax binding to CBP/p300 was shown to be necessary, but not sufficient to repress activity; p53 phosphorylation at serine 15 and 293 is also required (Pise-Masison et al, 1998; Van et al, 2001). These results have fueled an ongoing debate over the mechanisms and pathways involved in Tax-mediated suppression of p53 function and many more studies will be required to fully resolve this issue.…”