Novel BTB/POZ domain zinc-finger protein, LRF, is a potential target of the LAZ-3/BCL-6 oncogene

Abstract

BTB/POZ-domain C 2 H 2 zinc(Zn)-®nger proteins are encoded by a subfamily of genes related to the Drosophila gap gene kruÈppel. To date, two such proteins, PLZF and LAZ-3/BCL-6, have been implicated in oncogenesis. We have now identi®ed a new member of this gene subfamily which encodes a 62 kDa Zn-®nger protein, termed LRF, with a BTB/POZ domain highly similar to that of PLZF. Both human and mouse LRF genes, which localized to syntenic chromosomal regions (19p13.3 and 10B5.3, respectively), were widely expressed in adult tissues and cell lines. At approximately 9.5 ± 10.0 days of embryonic development, the mouse LRF gene was expressed in the limb buds, pharyngeal arches, tail bud, placenta and neural tube. The LRF protein associated in vivo with LAZ-3/BCL-6, but not with PLZF to which it was more related. Although the LRF, or LAZ-3/BCL-6, BTB/POZ domain could readily homodimerize, no heterodimerization was detected in vivo between the LRF and LAZ-3/BCL-6 BTB/POZ domains and interaction between full length LRF and LAZ-3/BCL-6 required the presence of both the BTB/POZ domain and Zn-®ngers in each partner protein. As expected from the above results, LRF and LAZ-3/BCL-6 also colocalized with each other in the nucleus. Taken together, our ®ndings suggest that BTB/ POZ-domain Zn-®nger proteins may function as homo and heterodimeric complexes whose formation, and hence the resultant eect on transcription of their downstream target genes, is determined by the levels and expression domains of a given partner protein.

POZ-, AT-hook-, and Zinc Finger-containing Protein (PATZ) Interacts with Human Oncogene B Cell Lymphoma 6 (BCL6) and Is Required for Its Negative Autoregulation

“…We first showed that PATZ and BCL6 bind to each other. This finding is consistent with the notion that POK proteins, such as PATZ and BCL6, commonly aggregate in large nuclear complexes by self-interaction, as heterodimers with other POK proteins and in association with unrelated partners, such as transcriptional corepressors, as a way to extend the repertoire of their target genes and/or the ways they act on their expression (29). BCL6 is the most commonly altered proto-oncogene in non-Hodgkin lymphomas, the majority of which derive from normal GC B cells (30).…”

PLZF induces megakaryocytic development, activates Tpo receptor expression and interacts with GATA1 protein

“…PLZF is a DNA-binding protein of about 80 to 90 kDa, that can be phosphorylated on serine and threonine residues (Chen et al, 1993b;Melnick and Licht, 1999;Reid et al, 1995). PLZF belongs to a protein family characterized by the presence of a BTB/ POZ domain (Li et al, 1997;Bardwell and Treisman, 1994;Ahmad et al, 1998) involved in heterodimerization (Dong et al, 1996;Koken et al, 1997;Davies et al, 1999;Hoatlin et al, 1999) and colocalization with other oncogenes (Dhordain et al, 2000).…”

Role of LRF/Pokemon in lineage fate decisions

“…Recently, however, the inventory of LRF/Pokemon interactors has been expanded to include other transcription factors such as tumor protein p53 (TP53), androgen receptor, specificity protein 1, BCL6, sex determining region Y-box 9 (SOX9), and growth factor independent 1, thereby suggesting an indirect transcriptional repressive activity of LRF on specific subclasses of genes ( Figure 1B). [10][11][12][13][14][15][16][17][18] These findings in turn highlight LRF as a key node for the transcriptional regulation of fundamental pathways involved in cell cycle control, apoptosis, and cell fate decision.…”

“…Finally, the poorly conserved hinge region between the POZ and ZF domains, as well as the C terminus at the end of the ZFs domains, are often the targets of posttranslational modifications responsible for the regulation of protein function ( Figure 1A). [10][11][12][13][14][15][16][17][18] Multiple POK proteins, LRF included, have been shown to act as transcriptional repressors by directly binding specific consensus sequences on DNA and interacting with corepressors such as NCoR, SMRT, and Sin3a via the POZ domain at the N terminus. 19,20 For its part, LRF preferentially binds to the GC-rich sequence [(G/A)(C/A)GACCCC], as has been revealed by cyclic amplification and selection of target analysis, 21 gelshift assay, 22 and chromatin immunoprecipitation sequencing.…”