The LAZ3/BCL6 oncogene encodes a sequence-specific transcriptional inhibitor: a novel function for the BTB/POZ domain as an autonomous repressing domain

Abstract

Rearrangements and mutations of the LAZ3/BCL6 gene are the most frequent events associated with diffuse large-cell lymphoma, a particular class of non-Hodgkin's lymphomas. This gene encodes a putative regulatory protein with six COOH-terminal Krüppel-like zinc fingers and a NH2-terminal hydrophobic region, the so-called BTB/POZ domain, which mediates homo- as well as heterotypic interactions in other related proteins. Recently, a consensus binding sequence has been defined using the isolated LAZ3/BCL6 zinc finger region produced in bacteria. To understand the normal and oncogenic functions of LAZ3/BCL6, we examined its properties as a transcription factor. We thus demonstrated that its full-length product binds to the same consensus sequence, although the BTB/POZ domain decreases this activity, at least in vitro. In transient transfection experiments, the LAZ3/BCL6 protein exerts a repressive effect, both as a wild-type protein on its own target sequence and as a GAL-4 fusion protein. Furthermore, our results indicate that the BTB/POZ domain plays a prominent role in the mediation of this activity. Indeed, on the LAZ3/BCL6 cognate sequence, deletion of the BTB/POZ domain diminishes the repressive function. Conversely, as a GAL-4 chimera, the isolated LAZ3/BCL6 BTB/POZ domain appears nearly as efficient as the entire protein at inducing transcriptional repression. Taken together, these findings demonstrate that the LAZ3/BCL6 is a sequence-specific transcriptional repressor and point to a novel function for the BTB/POZ region, at least in LAZ3/BCL6, as an autonomous transcriptional inhibitory domain.