title: Retinoblastoma protein and the leukemia-associated PLZF transcription factor interact to repress target gene promoters.
abstract: Translocations of the retinoic acid receptor-alpha (RARalpha) locus with the promyelocytic leukemia zinc-finger (PLZF) or PML genes lead to expression of oncogenic PLZF-RARalpha or PML-RARalpha fusion proteins, respectively. These fusion oncoproteins constitutively repress RARalpha target genes, in large part through aberrant recruitment of multiprotein co-repressor complexes. PML and PML-RARalpha have previously been shown to associate with the retinoblastoma (Rb) tumour suppressor protein in its hypophosphorylated state. Here, we demonstrate that PLZF also interacts with Rb in vitro and in vivo. The interaction between PLZF and Rb is mediated through the Rb pocket and the region of PLZF that lies between its transcriptional repression (poxvirus and zinc-finger, POZ) and DNA-binding (zinc-finger) domains. In addition, Rb can simultaneously interact with PLZF and the E2F1 S phase-inducing transcription factor, suggesting that these proteins can exist in the same multiprotein complex. In contrast to the interaction of Rb with PML or E2F1, the PLZF-Rb interaction is not dependent on hypophosphorylation of Rb. These data are supported by chromatin immunoprecipitation analysis, which indicates that PLZF associates with the promoter region of CDC6, a known E2F/Rb target gene. Co-expression of PLZF and Rb results in enhancement of transcriptional repression of PLZF and E2F/Rb target genes, indicating functional co-operation between the two proteins. Both PLZF and Rb have been shown to function in stem cells and taken together these data suggest that interactions between PLZF and Rb could be important in stem cell biology.
authors.affiliation: Section of Haemato-Oncology, Institute of Cancer Research, Sutton, UK.
authors.forename: K
authors.initials: K
authors.lastname: Petrie
authors.forename: F
authors.initials: F
authors.lastname: Guidez
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.forename: L
authors.initials: L
authors.lastname: Howell
authors.forename: G
authors.initials: G
authors.lastname: Owen
authors.forename: Y P
authors.initials: YP
authors.lastname: Chew
authors.forename: S
authors.initials: S
authors.lastname: Parks
authors.forename: S
authors.initials: S
authors.lastname: Waxman
authors.forename: J
authors.initials: J
authors.lastname: Licht
authors.forename: S
authors.initials: S
authors.lastname: Mittnacht
authors.forename: A
authors.initials: A
authors.lastname: Zelent
mesh_terms: D047369:Chromatin Immunoprecipitation; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D016160:Retinoblastoma Protein; C092037:ZBTB16 protein, human