Abstract
We have previously shown that TPA activates HTLV-1 LTR in Jurkat T-cells by inducing the binding of Sp1-p53 complex to the Sp1 site residing within the Ets responsive region 1 (ERR-1) of the LTR and that this activation is inhibited by PKCalpha and PKCepsilon. However, in H9 T-cells TPA has been noted to activate the LTR in two consecutive stages. The first stage is activation is mediated by PKCetta and requires the three 21 bp TRE repeats. The second activation mode resembles that of Jurkat cells, except that it is inhibited by PKCdelta. The present study revealed that the first LTR activation in H9 cells resulted from PKCetta-induced elevation of non-phosphorylated c-Jun which bound to the AP-1 site residing within each TRE. In contrast, this TRE-dependent activation did not occur in Jurkat cells, since there was no elevation of non-phosphorylated c-Jun in these cells. However, we found that PKCalpha and PKCepsilon, in Jurkat cells, and PKCetta and PKCdelta, in H9 cells, increased the level of phosphorylated c-Jun that interacted with the Sp1-p53 complex. This interaction prevented the Sp1-p53 binding to ERR-1 and blocked, thereby, the ERR-1-mediated LTR activation. Therefore, this PKC-inhibited LTR activation started in both cell types after depletion of the relevant PKCs by their downregulation. In view of these variable activating mechanisms we assume that there might be additional undiscovered yet modes of HTLV-1 LTR activation which vary in different cell types. Moreover, in line with this presumption we speculate that in HTLV-1 carriers the LTR of the latent provirus may also be reactivated by different mechanisms that vary between its different host T-lymphocyte subclones. Since this reactivation may initiate the ATL process, understanding of these mechanisms is essential for establishing strategies to block the possibility of reactivating the latent virus as preventive means for ATL development in carriers.
Highlights
Adult T-cell leukemia (ATL) is etiologically associated with human T-cell leukemia virus type 1 (HTLV-1) infection [1,2]
In a previous study we have shown that the PKC-antagonized LTR activation in Jurkat cells is mediated by binding of an Sp1p53 complex to the Sp1 site located within the Ets responsive region 1 (ERR-1) of the LTR [49]
In exploring the mechanism of the PKC-antagonized mode of the LTR activation, we have found in our previous studies that in Jurkat cells TPA activates the LTR by inducing the formation of an Sp1-p53 complex which binds to an Sp1 site residing within the ERR-1 domain of the LTR [41,49]
Summary
Adult T-cell leukemia (ATL) is etiologically associated with human T-cell leukemia virus type 1 (HTLV-1) infection [1,2]. The multifunctional viral Tax oncoprotein is widely regarded as the critical factor for initiating the leukemic process leading to this malignancy This role of Tax is linked mainly to its abilities to activate constitutive expression of major regulatory factors like the NF-kB [12,13,14,15,16,17] and to impair the cellular genome stability, which are reflected by enhanced DNAmutagenesis and chromosomal aberrations, including chromosomal aneuploidy, on one hand [14,18,19,20,21,22] and protecting the cells from the DNA damage-induced apoptosis on the other hand [14,20,21,22,23,24,25]. Since similar correlation of ROS induction with genomic instability, cellular senescence and tumorigenesis has been reported for several oncogenes like Myc [27,28], Ras [29] and the EBV nuclear antigen-1 [30], it has been suggested that this pathway might be involved in the HTLV1leukemogensis
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