HTLV-1 Tax oncoprotein inhibits the estrogen-induced-ER α-Mediated BRCA1 expression by interaction with CBP/p300 cofactors.

BRCA1 is a multifunctional tumor suppressor, whose expression is activated by the estrogen (E2)-liganded ERα receptor and regulated by certain recruited transcriptional co-activators. Interference with BRCA1 expression and/or functions leads to high risk of breast or/and ovarian cancer. Another multifunctional protein, HTLV-1Tax oncoprotein, is widely regarded as crucial for developing adult T-cell leukemia and other clinical disorders.

Differential role of PKC-induced c-Jun in HTLV-1 LTR activation by 12-O-tetradecanoylphorbol-13-acetate in different human T-cell lines.

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.

Role of caspase 9 in activation of HTLV-1 LTR expression by DNA damaging agents.

Adult T-cell leukemia (ATL) is caused by HTLV-I. The viral Tax oncoprotein plays a central role in initiating the process to ATL. However, after infection HTLV-1 enters into latency, during which virus gene expression is very low, so that the level of Tax is likely insufficient for exerting its oncogenic activities.

The mechanism of HTLV-1 LTR activation by TPA varies in different human T-cell lines: role of specific PKC isoforms.

We demonstrate here that TPA activates HTLV-1 LTR expression in Jurkat and H9 T-cell lines, by strictly different mechanisms. In Jurkat cells this activation is exerted by a PKCalpha- and PKCvarepsilon-antagonized mechanism which operates through an Sp1 binding site residing within the Est responsive region 1 of the LTR. On the other hand, in H9 cells TPA activates the LTR by two consecutive mechanisms; the first depends on PKCeta activity and is exerted through the 21 bp repeats of the LTR, whereas the second is analogous to that observed in Jurkat cells, except that it is antagonized by PKCdelta.

HTLV-1 tax-induced NF-kappaB activation is synergistically enhanced by 12-O-tetradecanoylphorbol-13-acetate: mechanism and implications for Tax oncogenicity.

Nuclear factor kappa B (NF-kappaB) factors regulate a wide range of physiological and oncogenic processes. Normally, these factors are transiently activated by specific external signals which induce their dissociation from inhibitors of kappaB (IkappaB) and subsequent translocation to the nucleus where p65 links to the cyclic adenosine monophosphate response element binding protein (CBP)-p300 and P/CAF coactivators that are essential for its transcriptional activity. The pathogenic potential of human T-cell leukemia virus type 1 (HTLV-1) Tax protein is partly ascribed to its capacity to constitutively activate NF-kappaB factors because constitutive activity of these factors play an important role in the pathophysiology of adult T-cell leukemia (ATL) and tropical spastic paraparesis-HTLV-1 associated myelopathy (TSP-HAM).

Dose-dependent dual effect of HTLV-1 tax oncoprotein on p53-dependent nucleotide excision repair in human T-cells.

In this study we investigated the effect of Tax on nucleotide excision repair (NER) in human T-cell lines by using the host cell repair analysis of UVC-irradiated reporter plasmid. This analysis revealed a p53-dependent NER activity in wild type (w.t.

Functional inactivation of p53 by human T-cell leukemia virus type 1 Tax protein: mechanisms and clinical implications.

Human T-cell leukemia virus type 1 (HTLV-I) has been implicated with the etiology of adult T-cell leukemia (ATL) and certain other clinical disorders. Although the leukemogenic mechanism of HTLV-1 is not fully understood yet, the viral Tax protein is widely regarded as a key factor in this mechanism. Tax can modulate the synthesis or function of many regulatory factors which control a wide range of normal and oncogenic cellular processes and therefore, it acts as a potent oncoprotein.

Molecular mechanisms of cellular transformation by HTLV-1 Tax.

The HTLV Tax protein is crucial for viral replication and for initiating malignant transformation leading to the development of adult T-cell leukemia. Tax has been shown to be oncogenic, since it transforms and immortalizes rodent fibroblasts and human T-lymphocytes. Through CREB, NF-kappaB and SRF pathways Tax transactivates cellular promoters including those of cytokines (IL-13, IL-15), cytokine receptors (IL-2Ralpha) and costimulatory surface receptors (OX40/OX40L) leading to upregulated protein expression and activated signaling cascades (e.

High levels of cytoplasmic HTLV-1 Tax mutant proteins retain a Tax-NF-kappaB-CBP ternary complex in the cytoplasm.

The oncogenic potential of HTLV-1 Tax protein is partially ascribed to its capacity to activate NF-kappaB. The current view is that Tax acts first in the cytoplasm to dissociate NF-kappaB factors from the IkappaB proteins and enable their nuclear translocation, then Tax links p65(RelA), within the nucleus, to CBP/p300 and P/CAF, which are essential for its optimal transcriptional activity. Our present study challenges the paradigm that Tax-p65(RelA)-CBP/p300 assembly occurs in the nucleus.

Implications of the evolution pattern of human T-cell leukemia retroviruses on their pathogenic virulence (Review).

Simian retroviruses pose a serious threat to public health, as two human pathogenic retroviruses, HIV and HTLV, have been already proved to originate from such non-human viruses. Therefore, studying their natural prevalence among wild non-human primates is important for planning strategies to prevent the emergence of additional human retroviral pathogens. This article is focused on tracing the origin and evolution of the human T-cell leukemia viruses HTLV-I and HTLV-II in comparison to that of the simian lymphotropic viruses STLV-I, STLV-II and STLV-L, which are phylo-genically classified into a common group called primate T-lymphotropic viruses (PTLV).

Role of Tax protein in human T-cell leukemia virus type-I leukemogenicity.

HTLV-1 is the etiological agent of adult T-cell leukemia (ATL), the neurological syndrome TSP/HAM and certain other clinical disorders. The viral Tax protein is considered to play a central role in the process leading to ATL. Tax modulates the expression of many viral and cellular genes through the CREB/ATF-, SRF- and NF-kappaB-associated pathways.

Activation of simian virus 40 promoter by HTLV-I Tax protein: role of NF-kappaB and CBP.

HTLV-I is implicated with adult T-cell leukemia and certain other clinical disorders. The viral Tax protein is regarded as a key element in HTLV-I pathogenicity due to its ability to activate a wide variety of cellular regulatory factors. As such, Tax may likely activate also latent infection of certain other pathogenic viruses whose expression is modulated by cellular transcription factors.

Role of protein kinase C and the Sp1-p53 complex in activation of p21(WAF-1) expression by 12-O-tetradecanoylphorbol-13-acetate in human T cells.

Previous reports have shown that, in certain cell types, p21(WAF-1), which plays a central role in cell proliferation, can be activated by HTLV-I Tax protein and by TPA. Tax and TPA are also known to stimulate HTLV-I gene expression. Since cell proliferation has a major impact on HTLV-I replication, it was of interest to investigate their effect on p21(WAF-1) in human T cells, which are the main target of HTLV-I in human infection.

Activation of HTLV-I long terminal repeat by apoptosis inducing agents: mechanism and implications for HTLV-I pathogenicity (review).

HTLV-I is the etiological agent of adult T-cell leukemia (ATL), tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM) and certain other clinical disorders. After infection in human the virus enters into a latent state, in which very low viral gene expression can be detected. On the other hand several major characteristics of ATL and TSP/HAM indicate that their genesis requires activation of the dormant virus.