In HTLV 1 infected T cell lines, upregulated p21CIP1 WAF1 may potentially function as an assembly factor for the cyclin D2 cdk4 complex, and the p21 cyclin D2 cdk4 complex may not act as an inhibitory complex but in stead may allow the increased phosphorylation never of Rb and accelerated progression into S phase. In the present study, Tax mediated G1 arrest occurred in human papilloma virus type 18 transformed HeLa cells, in which the Rb pathway was activated by repression of HPV 18 E7. Indeed, in cells trans fected with the control vector, the majority of Rb was in the hyperphosphorylated form ppRb. By contrast, an accumulation of hypo and or unpho sphorylated form pRb was observed in Tax expressing HeLa cells, which is in contrast to the results of study showing that Tax increased the phosphorylation of Rb family members.

Therefore, there is a strong possi bility that Tax activated p21CIP1 WAF1 may function to inhibit the cyclin D2 cdk4 complex, thereby inducing cell cycle arrest. Our microarray result also shows that Tax upregulated the expression of BCL6 gene encodes a sequences specific transcriptional repressor by 2. 7 fold. This sup ported by the findings in previous study, which described that an interaction of Tax with the POZ do main of BCL6 enhances the repressive activity of BCL6 and increased the levels of apoptosis induced by BCL6 in osteosarcoma cells. The BCL6 POZ domain mediates transcriptional repression by interacting with several corepressors including silencing mediator for retinoid and thyroid receptor and nuclear hormone receptor cor epressor, BCL6 corepressor together with many histone deacetylases.

BCL6 colocalizes with these corepressors in punctate nuclear structures that have been identified as sites of ongoing DNA replication. Interestingly, BCL6 appeared to recruite Tax into punctate nuclear structures and significantly downregulate both basal and Tax induced NF kB and long terminal repeat activation. Thus, the high expression of BCL6 in HTLV infected cells may contribute to the silencing of viral gene ex pression and to the long clinical latency associated with HTLV infection. This study allows greater understanding of the bio logical events affected by HTLV 1 Tax, particularly the regulation of cellular proliferation and apoptosis.

Since we found evidence of several similarities, as well as dif ferences, between Tax expressing HeLa cells and HTLV infection in T cell lines, we believe that the overexpres sion of Tax will be useful for preliminary studies on the effects of HTLV infection in T cell lines. However, since Zane et al. recently demonstrated that infected CD4 T cells Carfilzomib in vivo are positively selected for cell cycling but not cell death, our experimental approaches in HeLa cells may not be reflective of normal physiology of Tax or HTLV 1 in vivo infected cells.