51. 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
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Claudio Arra, Simon D. Wagner, Antonella Federico, Raffaela Pero, Luigi Del Vecchio, Teresa Valentino, Vasiliki Papadopoulou, Simona Keller, Dario Palmieri, Andres J. Klein-Szanto, Alfredo Fusco, Donatella Montanaro, Tiziana Angrisano, Carlo M. Croce, Francesca Lembo, Renato Franco, Monica Fedele, Lorenzo Chiariotti, Pero, Raffaela, Palmieri, D, Angrisano, Tiziana, Valentino, T, Federico, A, Franco, R, Lembo, Francesca, Klein Szanto, Aj, DEL VECCHIO, Luigi, Montanaro, D, Keller, Simona, Arra, C, Papadopoulou, V, Wagner, Sd, Croce, Cm, Fusco, Alfredo, Chiariotti, Lorenzo, Fedele, M., Pero, R, Angrisano, T, Franco, Renato, Lembo, F, Del Vecchio, L, Keller, S, Fusco, A, and Chiariotti, L
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Chromatin Immunoprecipitation ,Lymphoma, B-Cell ,Kruppel-Like Transcription Factors ,lymphoma ,Biology ,AT-hook ,DNA-binding protein ,Biochemistry ,Cell Line ,Mice ,Transactivation ,Krüppel ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Gene Regulation ,Autoregulation ,Withdrawals/Retractions ,B-cell lymphoma ,Transcription factor ,Molecular Biology ,DNA Primers ,Mice, Knockout ,Regulation of gene expression ,Zinc finger ,Base Sequence ,Oncogene ,Reverse Transcriptase Polymerase Chain Reaction ,Chemistry ,Germinal center ,Cell Biology ,medicine.disease ,BCL6 ,Molecular biology ,DNA-Binding Proteins ,Repressor Proteins ,Proto-Oncogene Proteins c-bcl-6 ,Cancer research ,Additions and Corrections ,Protein Binding - Abstract
The PATZ1 gene encoding a POZ/AT-hook/Kruppel zinc finger (PATZ) transcription factor, is considered a cancer-related gene because of its loss or misexpression in human neoplasias. As for other POZ/domain and Kruppel zinc finger (POK) family members, the transcriptional activity of PATZ is due to the POZ-mediated oligomer formation, suggesting that it might be not a typical transactivator but an architectural transcription factor, thus functioning either as activator or as repressor depending on the presence of proteins able to interact with it. Therefore, to better elucidate PATZ function, we searched for its molecular partners. By yeast two-hybrid screenings, we found a specific interaction between PATZ and BCL6, a human oncogene that plays a key role in germinal center (GC) derived neoplasias. We demonstrate that PATZ and BCL6 interact in germinal center-derived B lymphoma cells, through the POZ domain of PATZ. Moreover, we show that PATZ is able to bind the BCL6 regulatory region, where BCL6 itself acts as a negative regulator, and to contribute to negatively modulate its activity. Consistently, disruption of one or both Patz1 alleles in mice causes focal expansion of thymus B cells, in which BCL6 is up-regulated. This phenotype was almost completely rescued by crossing Patz1(+/-) with Bcl6(+/-) mice, indicating a key role for Bcl6 expression in its development. Finally, a significant number of Patz1 knock-out mice (both heterozygous and homozygous) also develop BCL6-expressing lymphomas. Therefore, the disruption of one or both Patz1 alleles may favor lymphomagenesis by activating the BCL6 pathway.