In resting T lymphocytes, the transcription factor NF-B isHuman T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia, an aggressive and often fatal malignancy of activated CD4 ϩ T lymphocytes (54, 82). This oncogenic retrovirus encodes a 40-kDa protein, termed Tax, which appears to play a central role in the process of neoplastic transformation (31,50,55,69,75). In this regard, Tax has the capacity to constitutively activate members of the NF-B/Rel family of transcription factors (5,44,59). This virus-host interplay confers Tax inducibility to a set of NF-Bresponsive cellular genes that are normally transcribed at high levels in response to T-cell activation signals. These genes include those encoding the growth factor interleukin-2 (IL-2) and the alpha subunit of its high-affinity receptor (19,35,39,45,67; for reviews, see references 27 and 28). Recent studies with mice transgenic for the tax gene suggest that the constitutive nuclear pattern of NF-B expression in HTLV-1-infected cells is required to maintain a state of deregulated growth (40). However, the precise mechanism by which Tax induces NF-B remains unclear.The prototypic form of NF-B is a heterodimeric complex containing p50 (NF-B1) and RelA (p65) (4,12,26,38,46,52,57). In resting T lymphocytes, NF-B is sequestered in the cytoplasm by virtue of its association with members of a set of inhibitory proteins, including IB␣ (2-4, 9, 23). During normal T-cell activation, IB␣ is rapidly phosphorylated at Ser-32 and Ser-36 (13, 14, 78), which is a prerequisite for targeting this inhibitor to the ubiquitin-proteasome pathway (16, 62; reviewed in reference 22). Several lines of evidence indicate that Tax stimulates the phosphorylation and degradation of IB␣ via a similar mechanism. First, IB␣ mutants containing alanine substitutions at Ser-32 and Ser-36 escape from proteolytic breakdown and prevent NF-B activation in Tax-expressing cells (13). Second, Tax fails to activate latent NF-B complexes containing mutant forms of IB␣ that are defective for ubiquitination (62). Third, point mutations in Tax that ablate its NF-B-inducing activity also impair its ability to stimulate IB␣ turnover (13). Fourth, phosphorylated IB␣ accumulates in Tax-expressing cells following treatment with an inhibitor of the proteasome (13). Together, these findings indicate that cytoplasmic NF-B complexes containing IB␣ serve as a major cellular target of HTLV-1 Tax.Recent molecular cloning studies have revealed another conditionally labile isoform of IB, termed IB␤, which has significant sequence homology with IB␣ (77). Although IB␣ and IB␤ likely interact with the same set of NF-B/Rel family members, it appears that these two inhibitors display distinct responses to different inducers of NF-B activity (77). As previously reported (77), agonists that stimulate a transient pattern of NF-B activity promote the selective breakdown of IB␣. In contrast, agents that elicit a persistent NF-B response, including bacterial lipopolysaccharide (LPS) and IL-1, are as...

Transient expression of I2PP2A, a potent inhibitor of protein phosphatase 2A (PP2A), in HEK-293 cells increased the concentration and DNA binding of the proto-oncogene c-Jun. In contrast, expression of the catalytic subunit of PP2A (PP2AC) markedly decreased the concentration and DNA binding of c-Jun. Expression of I2PP2A also increased the transcriptional activity of activator protein-1, and this effect was diminished in a dose-dependent manner by expression of PP2AC. Densitometric analysis following Western blotting of extracts with antibodies specific for phospho-Ser63 and Ser73 suggests that the effects of I2PP2A and PP2AC expression might be mediated, in part, by changes in the phosphorylation of c-Jun at Ser63. The results indicate that I2PP2A elicits effects that are consistent with it acting as an inhibitor of PP2A in intact cells, and suggest that PP2A might exhibit site selectivity with respect to c-Jun phosphorylation.

Transient expression of I2PP2A, a potent inhibitor of protein phosphatase 2A (PP2A), in HEK-293 cells increased the concentration and DNA binding of the proto-oncogene c-Jun. In contrast, expression of the catalytic subunit of PP2A (PP2AC) markedly decreased the concentration and DNA binding of c-Jun. Expression of I2PP2A also increased the transcriptional activity of activator protein-1, and this effect was diminished in a dose-dependent manner by expression of PP2AC. Densitometric analysis following Western blotting of extracts with antibodies specific for phospho-Ser63 and Ser73 suggests that the effects of I2PP2A and PP2AC expression might be mediated, in part, by changes in the phosphorylation of c-Jun at Ser63. The results indicate that I2PP2A elicits effects that are consistent with it acting as an inhibitor of PP2A in intact cells, and suggest that PP2A might exhibit site selectivity with respect to c-Jun phosphorylation.