Downregulation of proapoptotic Bim augments IL‐2‐independent T‐cell transformation by human T‐cell leukemia virus type‐1 Tax

Abstract

Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion–induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo.

Dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth in ATL

“…The growth inhibitory effect of DUSP5 was stronger in MT-1 cells than in TL-Om1 cells ( Figure 5 B-C). This could be because of differences in the dependency on ERK signaling for cell growth: p-ERK1/2 levels are higher in MT-1 cells than in TL-Om1 cells 54 ( supplemental Figure 9 ). Thus, inactivation of ERK signaling by DUSP5 is involved in the mechanism underlying the effect of combination therapy on inhibiting cell growth.…”

Mechanisms of Oncogenesis by HTLV-1 Tax

“…Interestingly, HBZ also promotes MCL-1 stabilization by disrupting the interaction between CUL1 and Skp1 in the SCF (Skp, Cullin, F-box) ubiquitin ligase complex [159]. Proapoptotic BCL-2-like protein 11 (BCL2L11; commonly called BIM) is downregulated in ATLL cell lines both at the mRNA level and through BIM protein degradation by Tax; re-expression of BIM induced apoptosis in ATLL cell lines [160]. HBZ has been shown to suppress transcription of the Bim gene by inhibiting the function of the FoxO3a transcription factor [161].…”

Modes of Human T Cell Leukemia Virus Type 1 Transmission, Replication and Persistence

“…Inhibition of Akt in HTLV-1-transformed cells decreases phosphorylated Bad and induces caspase-dependent apoptosis [ 96 ]. Stimulation of PI3K/Akt by Tax activates HiF-1 (hypoxia-inducible factor 1) [ 97 ], reduces expression of proapoptotic Bim and Bid and promotes IL-2 independent growth [ 98 ] and finally increases Bcl3 whose expression is associated with the growth of infected cells [ 99 ]. HBZ inhibits Tax-dependent activation of the PI3K/Akt pathway and downstream anti-apoptotic properties [ 100 ].…”