Retinoblastoma Protein and the Leukemia-Associated PLZF Transcription Factor Interact To Repress Target Gene Promoters.

Abstract

Translocations of the retinoic acid receptor alpha (RARA) locus with the PLZF or PML genes lead to expression of oncogenic PLZF-RARα or PML-RARα fusion proteins, respectively. These fusion oncoproteins constitutively repress RARα target genes, in large part through aberrant recruitment of multiprotein co-repressor complexes. PML and PML-RARα 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 (POZ) and DNA binding (zinc-finger) domains. Additionally, 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 between PML or E2F1 with Rb, the PLZF-Rb interaction is not dependent on hypophosphorylation of Rb. The interaction between PLZF and Rb is further underlined by chromatin immunoprecipitation analysis of PLZF binding to genomic DNA, which shows that PLZF associates with genes controlling cell proliferation known to be regulated by Rb and E2F (for example cdc6). Co-expression of PLZF and Rb results in enhancement of transcriptional repression of PLZF and E2F target genes, indicating functional co-operation between the two proteins. Both PLZF and Rb have been shown to have roles in stem cell biology and, taken together, these data provide a plausible scenario in which interactions between PLZF and Rb function in stem cell commitment or maintenance and self-renewal. The oncogenic PLZF-RARα fusion also interacts with Rb, suggesting that deregulation of Rb function may be a factor in the molecular pathogenesis of PLZF-RARα associated acute promyelocytic leukemia.

The epigenetic regulator PLZF represses L1 retrotransposition in germ and progenitor cells

“…These two mechanisms are important for maintaining the tight repressive state, which are considered as the major players involved in direct (Beck et al, 2010;Ewing and Kazazian, 2011) DNA interacting proteins, besides PLZF, have been reported to bind to the L1 retrotransposon including Runx3, p53 and SRY associated with the activation of L1 transcription (Tchénio et al, 2000;Yang et al, 2003;Harris et al, 2009). Until now, only one other transcription factor, the retinoblastoma protein (Rb), has been reported to induce L1 transcriptional repression by binding to the L1 promoter (Montoya-Durango et al, 2009) and we have previously shown that Rb and PLZF factors could cooperate to repress specific target promoters (Petrie et al, 2008). In this study, we show that PLZF is able to bind a specific DNA binding site, located outside the L1 promoter, to recruit proteins with epigenetic enzymatic activities (HDAC1 and DNMT1) inducing specific histone deacetylation and DNA methylation.…”

Concise Review: Balancing Stem Cell Self-Renewal and Differentiation with PLZF

“…HDACs participate in transcriptional repression of PLZF by deacetylating histones, resulting in local modification of chromatin structure . PLZF physically interacts with HDAC1 , HDAC4 , and Rb for PLZF‐mediated repression. PLZF represses transcription of p53 and decreases p53 protein stability by ubiquitination through corepressor HDACs complex .…”

Emerging Concept in DNA Methylation: Role of Transcription Factors in Shaping DNA Methylation Patterns

“…ZBTB16 targets these L1 elements by interacting both with the DNA and the L1 RNA, leading to the recruitment of DNMT1 and silencing of L1 retro‐transposition (Puszyk et al, ). Intriguingly, retinoblastoma protein (Rb) also represses L1 elements and it was previously shown that it interacts with ZBTB16 (Petrie et al, ). ZBTB16 regulates the expression of both protein‐coding genes and DNA repeats.…”