title: 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.
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.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II and Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
authors.forename: Raffaela
authors.initials: R
authors.lastname: Pero
authors.forename: Dario
authors.initials: D
authors.lastname: Palmieri
authors.forename: Tiziana
authors.initials: T
authors.lastname: Angrisano
authors.forename: Teresa
authors.initials: T
authors.lastname: Valentino
authors.forename: Antonella
authors.initials: A
authors.lastname: Federico
authors.forename: Renato
authors.initials: R
authors.lastname: Franco
authors.forename: Francesca
authors.initials: F
authors.lastname: Lembo
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.forename: Luigi
authors.initials: L
authors.lastname: Del Vecchio
authors.forename: Donatella
authors.initials: D
authors.lastname: Montanaro
authors.forename: Simona
authors.initials: S
authors.lastname: Keller
authors.forename: Claudio
authors.initials: C
authors.lastname: Arra
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Papadopoulou
authors.forename: Simon D
authors.initials: SD
authors.lastname: Wagner
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Chiariotti
authors.forename: Monica
authors.initials: M
authors.lastname: Fedele
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C084103:BCL6 protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; C412784:PATZ1 protein, human; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins