Disease relevance of ZBTB16

• The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein [1].
• A comparison of the PLZF, Bcl-6, and the FAZF (Fanconi anemia zinc finger)/ROG protein shows that variations in the BTB pocket result in differential affinity for corepressors, which predicts the potency of transcriptional repression [2].
• The PLZF gene was identified first by its fusion with the retinoic acid receptor alpha gene in the t(11;17) translocation associated with a retinoic acid resistant form of acute promyelocytic leukemia (APL) [3].
• PLZF is related to another POK protein, LAZ3(BCL6), which is structurally altered, and presumably misexpressed, in many non-Hodgkin lymphoma (NHL) cases [4].
• The PLZF-RAR alpha fusion protein contains an approximately 120-amino-acid N-terminal motif (called the POZ domain), which is also found in a variety of zinc finger proteins and a group of poxvirus proteins and which mediates protein-protein interactions [5].

High impact information on ZBTB16

• Two rare variants of APL have been described, in which RARA is fused to one of two other genes, PLZF and NPM [6].
• Mutant forms of RARalpha, created by chromosomal translocations with either the PML (for promyelocytic leukaemia) or the PLZF (for promyelocytic leukaemia zinc finger) locus, are oncogenic and result in human acute promyelocytic leukaemia (APL) [7].
• PLZF-RARalpha contains a second, RA-resistant binding site in the PLZF amino-terminal region [8].
• Strikingly, BCoR interacts selectively with the POZ domain of BCL-6 but not with eight other POZ proteins tested, including PLZF [9].
• Further molecular analysis of this patient showed a rearrangement between the RAR alpha gene and a newly discovered zinc finger gene named PLZF (promyelocytic leukemia zinc finger) [10].

Chemical compound and disease context of ZBTB16

• Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-alpha and the transcriptional repressor PLZF [11].
• CONCLUSIONS: The above observations indicate that PLZF is an androgen-responsive gene with anti-proliferative activity in prostate cancer cells [12].
• Cyclin A expression, cell growth kinetics, and cell cycle were analysed in stable clones of the Burkitt lymphoma (BL) B-cell line DG75 with inducible expression of PLZF, generated using the tetracycline-regulated expression system [13].

Biological context of ZBTB16

• PLZF associates with p300 in vivo, and its ability to repress transcription is specifically dependent on HAT activity of p300 and acetylation of lysines in its C-terminal C2-H2 zinc finger motif [14].
• Here we report that the promyelocytic leukemia zinc finger (PLZF) protein can interact with GATA-2 and can modify its transactivation capacity [15].
• This is due to the fact that acetylation of PLZF activates its ability to bind specific DNA sequences both in vitro and in vivo [14].
• PLZF-mediated regulation of the cell cycle and transcriptional repression of the cyclin A2 gene were also dependent on sumoylation of PLZF on lysine 242 [16].
• The PLZF gene becomes fused to the retinoic acid receptor alpha gene as a result of the t(11, 17)(q23;q21) chromosomal translocation that is associated with acute promyelocytic leukemia [16].

Anatomical context of ZBTB16

• In transiently transfected cells and in a cell line derived from a patient with t(8;21) leukemia, PLZF and AML-1/ETO formed a tight complex [17].
• AML-1/ETO also excluded PLZF from the nuclear matrix and reduced its ability to bind to its cognate DNA-binding site [17].
• The fusion PLZF-RAR alpha gene found in this case, was not found in DNA obtained from the bone marrow of normals, APL with t(15;17) and in one patient with AML-M2 with a t(11;17) [10].
• These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicate the PLZF-RAR alpha fusion proteins in the molecular pathogenesis of APL [18].
• In addition, stable, inducible expression of PLZF in U937 cells inhibited the ability of 1,25(OH)(2)D(3) to induce surface expression of the monocytic marker CD14 and morphologic changes associated with differentiation [19].

Associations of ZBTB16 with chemical compounds

• The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor alpha in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation [1].
• Site-directed mutagenesis identified lysine 242 in the RD2 domain of human PLZF as the sumoylation site [16].
• Trichostatin A, a specific inhibitor of histone deacetylases, significantly reduces PLZF repression [3].
• Furthermore, PLZF-RARalpha could heterodimerize in vitro with the wild-type PLZF, suggesting that it may play a role in leukemogenesis by antagonizing actions of not only the retinoid receptors but also the wild-type PLZF and possibly other POZ-domain-containing regulators [20].
• The silencing mediator of retinoic and thyroid hormone receptors (SMRT) corepressor mediates transcriptional repression by interacting with transcription factors such as the promyelocytic leukemia zinc finger (PLZF) protein [21].

Physical interactions of ZBTB16

• Unexpectedly, the PLZF moiety itself can interact with SMRT corepressor [22].
• An acetylation site mutant of PLZF does not repress transcription and is functionally deficient in a colony suppression assay despite retaining its abilities to interact with corepressor/histone deacetylase complexes [14].
• The LIM-only protein DRAL/FHL2 interacts with and is a corepressor for the promyelocytic leukemia zinc finger protein [23].
• We show that FAZF is a transcriptional repressor that is able to bind to the same DNA target sequences as PLZF [24].
• It was found that PLZF interacts directly with VDR [19].

Co-localisations of ZBTB16

• Prior to cell culture, PLZF/RARalpha was found to exactly co-localize with PML onto PML nuclear bodies [25].

Regulatory relationships of ZBTB16

• Current topics in pharmacological research on bone metabolism: Promyelotic leukemia zinc finger (PLZF) and tumor necrosis factor-alpha-stimulated gene 6 (TSG-6) identified by gene expression analysis play roles in the pathogenesis of ossification of the posterior longitudinal ligament [26].

Other interactions of ZBTB16

• SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia [22].
• We found that ETO is one of the corepressors recruited by PLZF [1].
• This ATRA-insensitive interaction between N-CoR and PLZF-RARalpha was mediated by the N-terminal PLZF moiety of the chimera [27].
• A novel BTB/POZ transcriptional repressor protein interacts with the Fanconi anemia group C protein and PLZF [24].
• PLZF, like BCL6, strongly represses transcription initiated from different promoters [3].

Analytical, diagnostic and therapeutic context of ZBTB16

• A luciferase reporter gene assay suggested that SUMO-1 modification of this residue is required for transcriptional repression by PLZF, and an electrophoretic mobility shift assay showed that this modification increases the DNA binding activity of PLZF [16].
• A PLZF-cdc2 interaction was further demonstrated by co-immunoprecipitation and a biotin-streptavidin pull-down assay [28].
• Fluorescence in situ hybridization using a PLZF specific probe localized the PLZF gene to chromosomal band 11q23 [10].
• We further explored the effects of the NPM-RARalpha chimeric protein on the subcellular localization of PML, RXRalpha, NPM, and PLZF using immunofluorescent confocal microscopy [29].
• The colocalization and the reciprocal 'rescue' is the result of a direct interaction between LAZ3 and PLZF, as indicated by yeast two hybrid assays, in vitro immunoprecipitations, and GST pull down experiments [4].

References