Cell Type-specific E2F Activation and Cell Cycle Progression Induced by the Oncogene Product Tax of Human T-cell Leukemia Virus Type I

Abstract

The transactivator protein Tax of human T-cell leukemia virus type I plays an important role in the development of adult T-cell leukemia probably through modulation of growth regulatory molecules including p16INK4a . The molecular mechanism of leukemogenesis induced by Tax has yet to be elucidated. We analyzed Tax

Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I

“…Cells were harvested for staining DNA with propidium iodide, followed by¯ow Mechanism of cell cycle progression by HTLV-I Tax R Iwanaga et al suitable for this purpose, because it can be made quiescent by deprivation of IL-2 (Hori et al, 1987). We have reported that the expression of Tax in quiescent Kit 225 cells induced activation of endogenous E2F and cell cycle progression to S and G2/M phases (Ohtani et al, 2000). The same results were obtained with phytohemagglutinin-stimulated peripheral blood lymphocytes, which also grow in the presence of IL-2, indicating that the ability of Tax to stimulate cell cycle progression is not speci®c to Kit 225 cells.…”

“…We previously reported that expression of HTLV-I Tax in the human T-cell line Kit 225, which was made quiescent by deprivation of IL-2, caused cell cycle progression at 48 h after infection with the Taxexpressing recombinant adenovirus (Ohtani et al, 2000). To examine biochemical events associated with Tax-induced cell cycle progression, we ®rst compared the kinetics of cell cycle progression induced by Tax with that by IL-2.…”

Molecular mechanisms of cellular transformation by HTLV-1 Tax

“…Tax activates Cdk4, Cdk6 and Cdk2 leading to phosphorylation of the retinoblastoma (Rb) tumor suppressor family proteins and freeing E2F Iwanaga et al, 2001). Tax can also increase E2F (Ohtani et al, 2000) in part through upregulation of the E2F-1 promoter via an ATF binding site (Lemasson et al, 1998). Several mechanisms may account for Tax's G1-S phase stimulatory action including (1) transcriptional upregulation of cyclin D2, (2) activation of kinases by direct binding of the kinase holoenzyme complex, and (3) repression of Cdk inhibitors (Figure 2).…”

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

“…The ability of Tax to directly alter the ratio of Rbbound and -unbound E2F results in activation of E2F-dependent transcription (Lemasson et al, 1998;Ohtani et al, 2000), thereby propelling the cell cycle through G 1 . Interestingly, Tax has also been shown to directly bind to the hypophosphorylated form of Rb and facilitate proteasomal degradation (Kehn et al, 2005).…”