THE LAZ3 BCL6 ONCOGENE ENCODES A SEQUENCE-SPECIFIC TRANSCRIPTIONAL INHIBITOR - A NOVEL FUNCTION FOR THE BTB/POZ DOMAIN AS AN AUTONOMOUS REPRESSING DOMAIN/

Rearrangements and mutations of the LAZ3/BCL6 gene are the most freque nt events associated with diffuse large-cell lymphoma, a particular cl ass of non-Hodgkin's lymphomas. This gene encodes a putative regulator y protein with six COOH-terminal Kruppel-like zinc fingers and a NH2-t erminal hydrophobic region, the so-called BTB/POZ domain, which mediat es home- as well as heterotypic interactions in other related proteins . Recently, a consensus binding sequence has been defined using the is olated LAZ3/BCL6 zinc finger region produced in bacteria. To understan d the normal and oncogenic functions of LAZ3/BCL6, we examined its pro perties 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 tr ansfection experiments, the LAZ3/BCL6 protein exerts a repressive effe ct, both as a wild-type protein on its own target sequence and as a GA L-4 fusion protein. Furthermore, our results indicate that the BTB/POZ domain plays a prominent role in the mediation of this activity. Inde ed, on the LAZ3/BCL6 cognate sequence, deletion of the BTB/POZ domain diminishes the repressive function. Conversely, as a GAL-4 chimera, th e isolated LAZ3/BCL6 BTB/POZ domain appears nearly as efficient as the entire protein at inducing transcriptional repression. Taken together , is these findings demonstrate that the LAZ3/BCL6 is a sequence-speci fic transcriptional repressor and point to a novel function for the BT B/POZ region, at least in LAZ3/BCL6, as an autonomous transcriptional inhibitory domain.