OVERPRODUCTION OF NFKB2(LYT-1O) AND C-REL - A MECHANISM FOR HTLV-I TAX-MEDIATED TRANSACTIVATION VIA THE NF-KAPPA-B SIGNALING PATHWAY

Molecular, biochemical and epidemiological evidence implicate HTLV-I a s an etiologic agent of adult T cell leukemia (ATL). The Tax protein o f HTLV-I, a positive transcriptional activator of HTLV-I gene expressi on, is a viral oncogene that also increases transcription of cellular genes including GM-CSF, IL-2R alpha and IL-2. One of the cellular targ ets of the trans-activating effects of Tax is the NF-kappa B/Rel famil y of transcription factors, pleiotropic regulators of immunoregulatory , cytokine and viral gene expression. In this report, we demonstrate t hat NFKB2, (lyt-10) and c-Rel are overexpressed in HTLV-I infected and Tax-expressing cells and, together, account for the majority of the c onstitutive NF-kappa-B binding activity in these cells before and afte r PMA stimulation. Most importantly, we show a Tax-dependent correlati on between expression of NFKB2(p100) and processing to the DNA binding NFKB2(p52) form, induction of c-Rel, and trans-activation of NF-kappa B-mediated gene expression. Furthermore, the NFKB2 precursor is physi cally associated with c-Rel and with Tax in HTLV-I infected cells. We propose that NFKB2 synthesis and processing allows continuous nuclear expression of an otherwise cytoplasmic protein and, in conjunction wit h overexpression of c-Rel, NFKB2 alters the NF-kappa B signalling path way and contributes to leukemic transformation of T cells by HTLV-I.