Cell transformation by oncogenes leads to changes in gene expression. A key event in this process seems to be activation of the transcription factors AP-1 and PEA 3. Their synergistic activities are required for efficient activation of transcription from different promoters by many different oncogenes, serum growth factors and the tumour promoter TPA. We show here that the products of the ets-1 and -2 proto-oncogenes, whose biological function was previously unknown, are transcription factors that activate transcription through the PEA 3 motif. The p68c-ets-1 protein specifically binds to DNA and contains a transcriptional activation domain. The ets-like gene family therefore seems to encode a new family of transcription factors, apparently unrelated to other transcription factors. The p68c-ets-1 protein cooperates with c-Fos and c-Jun (components of AP-1) for activation of transcription from the oncogene-responsive domain of the polyoma enhancer, indicating that combined activity of all three oncoproteins could be involved in the response of cells to growth stimuli.

The LAZ3͞BCL6 (lymphoma-associated zinc finger 3͞B cell lymphomas 6) gene frequently is altered in non-Hodgkin lymphomas. It encodes a sequence-specific DNA binding transcriptional repressor that contains a conserved N-terminal domain, termed BTB͞POZ (bric-à-brac tramtrack broad complex͞pox viruses and zinc fingers). Using a yeast two-hybrid screen, we show here that the LAZ3͞BCL6 BTB͞ POZ domain interacts with the SMRT (silencing mediator of retinoid and thyroid receptor) protein. SMRT originally was identified as a corepressor of unliganded retinoic acid and thyroid receptors and forms a repressive complex with a mammalian homolog of the yeast transcriptional repressor SIN3 and the HDAC-1 histone deacetylase. Protein binding assays demonstrate that the LAZ3͞BCL6 BTB͞POZ domain directly interacts with SMRT in vitro. Furthermore, DNAbound LAZ3͞BCL6 recruits SMRT in vivo, and both overexpressed proteins completely colocalize in nuclear dots. Finally, overexpression of SMRT enhances the LAZ3͞BCL6-mediated repression. These results define SMRT as a corepressor of LAZ3͞BCL6 and suggest that LAZ3͞BCL6 and nuclear hormone receptors repress transcription through shared mechanisms involving SMRT recruitment and histone deacetylation.The LAZ3͞BCL6 (lymphoma-associated zinc finger 3͞B cell lymphomas 6) gene has been cloned by virtue of its frequent structural alteration in both diffuse large cell and follicular lymphomas (1-3). These alterations include translocations, small deletions, and point mutations. Most of them have been found in a genomic region, called the major translocation cluster, containing the first noncoding exon and the first downstream intron of the LAZ3͞BCL6 locus (4-8). It usually is proposed that such structural alterations lead to the deregulation of LAZ3͞BCL6 expression and, hence, contribute to lymphomagenesis (4, 7). The normal LAZ3͞BCL6 expression pattern suggests its implication in B cell differentiation and in the control of T cell-dependent immune response (9). Recent genetic experiments in mouse abrogating LAZ3͞BCL6 expression or leading to the expression of an inactive deleted version of this protein substantiate this hypothesis. Indeed, mice deficient for LAZ3͞BCL6 activity are devoid of germinal centers, present a Th2-type inflammatory disease and a defect in T cell-dependent antibody response (10, 11). Taken together, these results suggest that LAZ3͞BCL6-associated lymphomas may occur as a consequence of a deregulated LAZ3͞ BCL6 expression.The LAZ3͞BCL6 gene encodes a sequence-specific transcriptional repressor that harbors six C-terminal C2H2 krüp-pel-like zinc fingers. These zinc fingers are responsible for the sequence-specific DNA binding of the protein. At its Nterminal part, LAZ3͞BCL6 also contains an Ϸ130-aa conserved domain termed the BTB͞POZ (bric-à-brac tramtrack broad complex͞pox viruses and zinc fingers) domain (12,13). This domain has been identified in Ϸ40 proteins found in Metazoans and poxviruses (13). In LAZ3͞BCL6, the BTB͞ POZ domain mediates self-interaction an...