HTLV-1 Tax protein cooperates with Ras in protecting cells from apoptosis

Abstract

Tax protein of the human T-cell leukemia virus type 1 (HTLV-1) plays a critical role in HTLV-I-correlated diseases through its ability to deregulate the expression of a vast array of cellular genes. We have previously shown that Tax counteracts apoptosis induced by stimuli triggering mitochondria apoptotic pathway, most likely by activating CREB-mediated transcription and affecting the phosphorylation levels of CREB at Ser-133. Here, we report data that indicate the oncoprotein Ras as a possible mediator of Tax-induced apoptosis protection and suggest a possible role of Tax in Ras activation. In addition, using inhibitors of down stream effectors of Ras, we found that ERK signaling is the most relevant for Tax-mediated apoptosis protection. As a whole, our findings provide intriguing evidence of a possible link between Ras signaling and Tax capability to counteract apoptosis and to enhance P-CREB levels, and implicates a potential role for Ras in HTLV-1-induced diseases.

Rocaglamide breaks TRAIL resistance in HTLV-1-associated adult T-cell leukemia/lymphoma by translational suppression of c-FLIP expression

“…33,34 Recently, Ras-ERK signaling was shown to be particularly important for Taxmediated protection of cells from apoptosis. 35 Our study demonstrates that Roc can block the Ras-ERK signaling pathway and thereby downregulate c-FLIP expression through inhibition of eIF4E function, a key factor that controls the rate-limiting step of translation. 29 Although inhibition of eIF4E function will lead to inhibition of translation in general, only the expression levels of c-FLIP proteins were shown to be downregulated by Roc treatment.…”

“…In contrast, 100 nM of Roc-AR, which was shown to completely block 35 S-methionine incorporation (Figure 4b), showed no effect on protein synthesis in the rabbit reticulocyte cell-free system (Figure 4c). These data indicate that Roc does not directly inhibit the translation machinery, but rather acts through inhibition of the signaling pathway that is required for translation.…”

“…In parallel, cycloheximide (CHX) was used as a control, which inhibits protein biosynthesis by the ribosomal machinery. 28 The experiment showed that Roc-AR strongly inhibited 35 S-methionine incorporation with an IC 50 of approximately 30 nM (Figure 4b). These data suggest that Roc-AR may downregulate c-FLIP expression through inhibition of translation.…”

Contribution of Inducible Nitric Oxide Synthase to the Transformation of HTLV-1 Infected CD4+ T-Cells

“…Recent findings showed that iNOS expression promotes tumorigenesis in ER-negative breast cancer by a mechanism in which NO induces Snitrosylation of wild-type Ras, leading to phosphorylation and activation of the transcription factor Ets-1 through the Ras/MEK/ERK pathway [166]. Interestingly, the Ras protein has been shown to be involved in the survival of HTLV-1 infected cells [167,168]. Akt is another multifunctional regulatory protein that is also involved in cellular metabolism, proliferation and survival.…”

Human T-lymphotropic virus proteins and post-translational modification pathways

“…In Tax-expressing cells, Tax modulates and increases the phosphorylation (activation) of Ras and ERK kinases, thus facilitating cell proliferation [46] . In this context, Tax protects from apoptosis cooperating with Ras in activating ERK signaling [47] . Furthermore, Tax physically interacts, through its PDZ binding motif, and blocks the function of Erbin, negative regulator of the Ras-Raf-ERK pathway, enhancing the cell proliferation and the protection from apoptosis [48] .…”