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 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.
Deweindt
C
C
U124 INSERM, Institut de Recherches Sur le Cancer de Lille, France.
Albagli
O
O
Bernardin
F
F
Dhordain
P
P
Quief
S
S
Lantoine
D
D
Kerckaert
J P
JP
Leprince
D
D
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D002522:Chlorocebus aethiops; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005656:Fungal Proteins / Q000096:biosynthesis; D005786:Gene Expression Regulation; D015321:Gene Rearrangement; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009857:Oncogenes; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051560:Proto-Oncogene Proteins c-bcl-6; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase