Transcriptional up-regulation of the cyclin D2 gene and acquisition of newcyclin-dependent kinase partners in human T-cell leukemia virus type 1-infected cells

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adul t T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis. Tax(1) is a 40-kDa phosphoprotein, predominantly local ized in the nucleus of the host cell, which functions to transactivate both viral and cellular promoters. It seems likely that HTLV-1, through express ion of the viral regulatory protein Tax(1), provides some initial alteratio n in cell metabolism predisposing the development of ATL. Here, we demonstr ate that HTLV-1 infection in T-cell lines and patient samples causes overex pression of an early G(1) cyclin, cyclin D2. The transcriptional up-regulat ion of the cyclin D2 gene is due to activation of Tax on the cyclin D2 gene . More important, we find that overexpression of cyclin D2 is accompanied b y acquisition of new partners such as cyclin-dependent kinase 2 (cdk2), cdk 4, and cdk6 in infected cells, This is in contrast to uninfected T cells, w here cyclin D2 associates only with cdk6, Functional effects of these cycli n-cdk complexes in infected cells are shown by hyperphosphorylation of Rb a nd histone H1, indicators of active progression into S phase as well as cha nges in cellular chromatin and transcription machinery. These studies link HTLV-1 infection with changes of cellular cyclin gene expression, hence pro viding clues to development of T-cell leukemia.