Human T-cell leukemia virus type I Tax induces expression of the Rel-related family of kappa B enhancer-binding proteins: evidence for a pretranslational component of regulation

Abstract

The Tax protein of the human T-cell leukemia virus type I (HTLV-I) serves as a potent transcriptional activator of its own long terminal repeat as well as select cellular genes, including interleukin-2 and the alpha subunit of the interleukin-2 receptor. Tax activation of these two growth-related genes appears to involve the induced nuclear expression of DNA-binding proteins that specifically engage related kappa B enhancer elements present in the 5' regulatory regions of these genes. In human T cells, kappa B enhancer-binding activity has been discerned as an unexpectedly large family of UV cross-linked nucleoprotein adducts, termed p50, p55, p75, and p85. The protein components of each of these DNA-protein adducts have been shown to share structural similarity with the v-rel oncogene product. The p55 adduct is composed of the 50-kDa subunit of NF-kappa B derived from a 105-kDa precursor polypeptide, while the p50 adduct contains a smaller protein that is closely related to NF-kappa B p50. The p75 adduct contains the 65-kDa subunit of NF-kappa B, while the p85 adduct is composed of the human c-rel proto-oncogene product. We now demonstrate that HTLV-I Tax, in the absence of other viral pX gene products, is capable of inducing the nuclear expression of all four of these kappa B-binding proteins in human T cells, with most marked effects involving c-Rel and NF-kappa B p65. Tax induction of the nuclear expression of c-Rel and NF-kappa B p50 is regulated, at least in part, at a pretranslational level involving increases in c-rel and NF-kappa B p105 mRNA expression. To study the pattern of expression of these kappa B-specific proteins in cells infected with the whole HTLV-I, seven cloned HTLV-I-infected T-cell lines were established from the peripheral blood of patients with adult T-cell leukemia. Of note, only three of these seven cell lines produced Tax, and c-rel mRNA and nuclear protein expression was confined to these three cell lines. In contrast, NF-kappa B p50 and NF-kappa B p65 were constitutively expressed in the nuclei of all seven of the HTLV-I-infected cell lines, even in the absence of detectable Tax or other viral gene expression. These findings raise the possibility of an alternate, Tax-independent pathway for the induced nuclear expression of NF-kappa B p50 and NF-kappa B p65 following HTLV-I infection.