The pathogenic effect of human t-cell leukemia virus type i (htlv-1) in adult t‐cell leukemia/lymphoma is mediated through tax-stimulation of wnt signaling pathway
1. zabol university of medical science 2. zabol university of medical science 3. zabol university of medical science
Abstract
Introduction
Having a tight association with a variety of human diseases,(htlv‐1) a retrovirus that infects 20 million people worldwide, recently captured tremendous attentions and considerable number of researches are now on the way to identify a precise mechanism of action for this complex deltaretrovirus. htlv-1 was the first retrovirus to be shown to be the etiologic agent of a severe and fatal cd4+ lymphoproliferative disease, adult t‐cell leukemia/lymphoma (atll). it is well established that tax, which perturbs cell cycle regulation and modulates cellular gene expression has a critical role in the transformation of infected cells. given to the interconnection between tax and various oncogenic signaling pathways, it was of particular of interest to dissect whether tax regulatory protein could stimulate wnt axis, an important signaling pathway activated in acute leukemia.
Methods
We have chosen both the htlv-i-infected t-cell lines and the non-infected jurkat leukemic t cells. to investigate whether tax expression is correlated with alteration in the phosphorylation of gsk-3β and β-catenin,a critical components of wnt signaling ,immunoblotting was applied on extracts from htlv1-infected t-cell lines or human jurkat tcells transfected with tax cdna expression plasmid. next, rq-pcr was done to evaluate the mrna expression level of a large cohort wnt associated genes in both cell lines. to address the impact of tax on the regulation of cell cycle and apoptosis, dna content analysis and annexin-v staining were also performed, respectively.
Results
the results of the present study clearly demonstrated that tax-stimulated the wnt signaling pathway in both htlv-i-infected and tax-transfected human t cells is associated with the alteration in the phosphorylation level of gsk-3β and β-catenin. moreover, we found that tax not only down-regulated the transcriptional activity of p21 and p27, two well-known cyclin-dependent kinase inhibitors, resulting in progression of cell cycle, but also prevented apoptosis, through disturbing the balance between pro- and anti-apoptotic target genes.
Conclusion
taking these findings together, the aberrant activation of wnt axis is suggested to contribute to cellular immortalization and transformation induced by htlv‐1 infection.
