Deregulation of CBP mediated transcription by the HTLV-I tax protein

Abstract

Human T-cell leukemia virus, type I (HTLV-I) is a retrovirus that causes an aggressive form of leukemia. A viral transcription factor called Tax is essential for efficient transcription from the viral promoter. At the viral promoter, Tax works through the cellular transcription factor CREB and three CREB response elements, called viral CREs, to form a stable nucleoprotein complex. Recently, Tax was shown to interact with the coactivator CBP in vitro. Here we utilize transient transfection assays to show that CBP plays a functional role in Tax transactivation through the viral CRE in vivo. Furthermore, Tax activity is dependent on interaction with a specific domain of CBP called KIX. In addition to Tax, many cellular transcription factors bind to the KIX domain of CBP. We hypothesized that the high affinity binding of Tax to the KIX domain may occlude binding of these other factors, thus inhibiting transcription mediated through these factors in vivo. To test this hypothesis, we examined the interplay between Tax and c-jun, a second KIX binding factor. We observe reciprocal repression between Tax and c-jun in vivo and biochemical assays indicate that Tax competes with c-jun for binding to the KIX domain in vitro. Together, these data indicate that the Tax-KIX interaction has potential to disrupt other functional KIX interactions. We next hypothesized that coactivator competition may explain the observed transcriptional inactivation of the tumor suppressor p53 in HTLV-I infected cells. p53 was recently shown to utilize CBP to activate transcription making coactivator competition a likely mechanism. We show reciprocal repression between Tax and p53 in vivo and in vitro binding assays demonstrate that p53 binds the KIX domain of CBP. This interaction appears to be functional as expression of the KIX domain of CBP in vivo has a dominant negative effect on p53 activated transcription. Finally, we observe that Tax and p53 compete for KIX in vitro. In summary, Tax competes with p53 for the KIX domain of CBP thus inactivating p53 transcription function. This mechanism may extend to other transcription factor pathways and play a key role cellular transformation.