AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3939-3947 ◽  
Author(s):  
Ari Melnick ◽  
Graeme W. Carlile ◽  
Melanie J. McConnell ◽  
Adam Polinger ◽  
Scott W. Hiebert ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Zinc Finger ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Zinc Finger Protein ◽  
Promyelocytic Leukemia ◽  
Dominant Negative ◽  
Myelogenous Leukemia ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Dominant Negative Inhibitor

The AML-1/ETO fusion protein, created by the (8;21) translocation in M2-type acute myelogenous leukemia (AML), is a dominant repressive form of AML-1. This effect is due to the ability of the ETO portion of the protein to recruit co-repressors to promoters of AML-1 target genes. The t(11;17)(q21;q23)-associated acute promyelocytic leukemia creates the promyelocytic leukemia zinc finger PLZFt/RARα fusion protein and, in a similar manner, inhibits RARα target gene expression and myeloid differentiation. PLZF is expressed in hematopoietic progenitors and functions as a growth suppressor by repressing cyclin A2 and other targets. ETO is a corepressor for PLZF and potentiates transcriptional repression by linking PLZF to a histone deacetylase-containing complex. 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. In transient assays, AML-1/ETO blocked transcriptional repression by PLZF, even at substoichiometric levels relative to PLZF. This effect was dependent on the presence of the ETO zinc finger domain, which recruits corepressors, and could not be rescued by overexpression of co-repressors that normally enhance PLZF repression. AML-1/ETO also excluded PLZF from the nuclear matrix and reduced its ability to bind to its cognate DNA-binding site. Finally, ETO interacted with PLZF/RARα and enhanced its ability to repress through the RARE. These data show a link in the transcriptional pathways of M2 and M3 leukemia.

AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3939-3947 ◽  
Author(s):  
Ari Melnick ◽  
Graeme W. Carlile ◽  
Melanie J. McConnell ◽  
Adam Polinger ◽  
Scott W. Hiebert ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Zinc Finger ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Zinc Finger Protein ◽  
Promyelocytic Leukemia ◽  
Dominant Negative ◽  
Myelogenous Leukemia ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Dominant Negative Inhibitor

Abstract The AML-1/ETO fusion protein, created by the (8;21) translocation in M2-type acute myelogenous leukemia (AML), is a dominant repressive form of AML-1. This effect is due to the ability of the ETO portion of the protein to recruit co-repressors to promoters of AML-1 target genes. The t(11;17)(q21;q23)-associated acute promyelocytic leukemia creates the promyelocytic leukemia zinc finger PLZFt/RARα fusion protein and, in a similar manner, inhibits RARα target gene expression and myeloid differentiation. PLZF is expressed in hematopoietic progenitors and functions as a growth suppressor by repressing cyclin A2 and other targets. ETO is a corepressor for PLZF and potentiates transcriptional repression by linking PLZF to a histone deacetylase-containing complex. 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. In transient assays, AML-1/ETO blocked transcriptional repression by PLZF, even at substoichiometric levels relative to PLZF. This effect was dependent on the presence of the ETO zinc finger domain, which recruits corepressors, and could not be rescued by overexpression of co-repressors that normally enhance PLZF repression. AML-1/ETO also excluded PLZF from the nuclear matrix and reduced its ability to bind to its cognate DNA-binding site. Finally, ETO interacted with PLZF/RARα and enhanced its ability to repress through the RARE. These data show a link in the transcriptional pathways of M2 and M3 leukemia.

Interactions of GATA-2 with the promyelocytic leukemia zinc finger (PLZF) protein, its homologue FAZF, and the t(11;17)-generated PLZF–retinoic acid receptor alpha oncoprotein

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3404-3410 ◽  
Author(s):  
Shinobu Tsuzuki ◽  
Tariq Enver
Keyword(s):  
Retinoic Acid ◽  
Zinc Finger ◽  
Target Genes ◽  
Zinc Finger Protein ◽  
Retinoic Acid Receptor ◽  
Trichostatin A ◽  
Chromosomal Translocation ◽  
Promyelocytic Leukemia ◽  
Homologous Proteins ◽  
Promyelocytic Leukemia Zinc Finger

Abstract Transcription factor GATA-2 is implicated in the survival and growth of multipotential progenitors. Here we report that the promyelocytic leukemia zinc finger (PLZF) protein can interact with GATA-2 and can modify its transactivation capacity. Fanconi anemia zinc finger (FAZF), a PLZF-homologous protein that has been variously described as ROG (repressor of GATA), and TZFP (testis zinc finger protein) also interact with GATA-2. The zinc finger region of GATA-2 is required for binding to PLZF and FAZF, but distinct interfaces on the PLZF and FAZF molecules mediate the interaction, suggesting that GATA-2 activity is controlled by these 2 homologous proteins through distinct mechanisms. GATA-2 can also physically associate with the PLZF-RARα fusion protein generated by the t(11;17) chromosomal translocation associated with acute promyelocytic leukemia (APL). Functional experiments showed that this interaction has the capacity to render GATA-dependent transcription responsive to treatment with a combination of all-trans retinoic acid and the histone deacetylase inhibitor trichostatin A (TSA). This combination of drugs has been shown to stimulate the terminal differentiation of leukemic t(11;17)-associated APL blasts, raising the possibility that GATA target genes may be involved in the molecular pathogenesis of APL.

scholarly journals Physical and Functional Interactions of Human Endogenous Retrovirus Proteins Np9 and Rec with the Promyelocytic Leukemia Zinc Finger Protein

2007 ◽  
Vol 81 (11) ◽  
pp. 5607-5616 ◽  
Author(s):  
Miriam Denne ◽  
Marlies Sauter ◽  
Vivienne Armbruester ◽  
Jonathan D. Licht ◽  
Klaus Roemer ◽  
...  
Keyword(s):  
Germ Cell ◽  
Zinc Finger ◽  
Transcriptional Repression ◽  
Zinc Finger Protein ◽  
Germ Cell Tumors ◽  
Endogenous Retrovirus ◽  
Promyelocytic Leukemia ◽  
Human Endogenous Retrovirus ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Altered Expression

ABSTRACT Only few of the human endogenous retrovirus (HERV) sequences in the human genome can produce proteins. We have previously reported that (i) patients with germ cell tumors often make antibodies against proteins encoded by HERV-K elements, (ii) expression of the HERV-K rec gene in transgenic mice can interfere with germ cell development and induce carcinoma in situ, and (iii) HERV-K np9 transcript is overproduced in many tumors including breast cancers. Here we document that both Np9 and Rec physically and functionally interact with the promyelocytic leukemia zinc finger (PLZF) tumor suppressor, a transcriptional repressor and chromatin remodeler implicated in cancer and the self-renewal of spermatogonial stem cells. Interaction is mediated via two different central and C-terminal domains of Np9 and Rec and the C-terminal zinc fingers of PLZF. One major target of PLZF is the c-myc proto-oncogene. Coexpression of Np9 and Rec with PLZF abrogates the transcriptional repression of the c-myc gene promoter by PLZF and results in c-Myc overproduction, altered expression of c-Myc-regulated genes, and corresponding effects on cell proliferation and survival. Thus, the human endogenous retrovirus proteins Np9 and Rec may act oncogenically by derepressing c-myc through the inhibition of PLZF.

scholarly journals Promyelocytic Leukemia Zinc Finger Protein Regulates Interferon-Mediated Innate Immunity

Immunity ◽  
2009 ◽  
Vol 30 (6) ◽  
pp. 802-816 ◽  
Author(s):  
Dakang Xu ◽  
Michelle Holko ◽  
Anthony J. Sadler ◽  
Bernadette Scott ◽  
Shigeki Higashiyama ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Finger Protein

scholarly journals The ETO Protein Disrupted in t(8;21)-Associated Acute Myeloid Leukemia Is a Corepressor for the Promyelocytic Leukemia Zinc Finger Protein

2000 ◽  
Vol 20 (6) ◽  
pp. 2075-2086 ◽  
Author(s):  
Ari M. Melnick ◽  
Jennifer J. Westendorf ◽  
Adam Polinger ◽  
Graeme W. Carlile ◽  
Sally Arai ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Zinc Finger ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Myeloid Leukemia ◽  
Histone Deacetylase Inhibitors ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Acute Myeloid

ABSTRACT The ETO protein was originally identified by its fusion to the AML-1 transcription factor in translocation (8;21) associated with the M2 form of acute myeloid leukemia (AML). The resulting AML-1–ETO fusion is an aberrant transcriptional regulator due to the ability of ETO, which does not bind DNA itself, to recruit the transcriptional corepressors N-CoR, SMRT, and Sin3A and histone deacetylases. The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor α in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation. PLZF also mediates transcriptional repression through the actions of corepressors and histone deacetylases. We found that ETO is one of the corepressors recruited by PLZF. The PLZF and ETO proteins associate in vivo and in vitro, and ETO can potentiate transcriptional repression by PLZF. The N-terminal portion of ETO forms complexes with PLZF, while the C-terminal region, which was shown to bind to N-CoR and SMRT, is required for the ability of ETO to augment transcriptional repression by PLZF. The second repression domain (RD2) of PLZF, not the POZ/BTB domain, is necessary to bind to ETO. Corepression by ETO was completely abrogated by histone deacetylase inhibitors. This identifies ETO as a cofactor for a sequence-specific transcription factor and indicates that, like other corepressors, it functions through the action of histone deactylase.

scholarly journals The GTPase domain of Galphao contributes to the functional interaction of Galphao with the promyelocytic leukemia zinc finger protein

2009 ◽  
Vol 14 (1) ◽  
Author(s):  
Jung Won ◽  
Sung Ghil
Keyword(s):  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Promyelocytic Leukemia ◽  
Functional Interaction ◽  
Gtpase Domain ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Downstream Effector ◽  
Finger Protein ◽  
Family Based ◽  
G Protein Coupled

AbstractGo, one of the most abundant heterotrimeric G proteins in the brain, is classified as a member of the Gi/Go family based on its homology to Gi proteins. Recently, we identified promyelocytic leukemia zinc finger protein (PLZF) as a candidate downstream effector for the alpha subunit of Go (Gαo). Activated Gαo interacts with PLZF and augments its function as a repressor of transcription and cell growth. G protein-coupled receptor-mediated Gαo activation also enhanced PLZF function. In this study, we determined that the GTPase domain of Gαo contributes to Gαo:PLZF interaction. We also showed that the Gαo GTPase domain is important in modulating the function of PLZF. This data indicates that the GTPase domain of Gαo may be necessary for the functional interaction of Gαo with PLZF.

Mutation In Erythroid Specific Transcription Factor KLF1 Causes Hereditary Spherocytosis In the Nan (Neonatal Anemia) Hemolytic Anemia Mouse Model

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3217-3217
Author(s):  
Robert A White ◽  
Daniel P. Heruth ◽  
Troy Hawkins ◽  
Derek Logsdon ◽  
Margaret Gibson ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hemolytic Anemia ◽  
Zinc Finger ◽  
Target Genes ◽  
Zinc Finger Protein ◽  
Hereditary Spherocytosis ◽  
Competitive Inhibition ◽  
Conflicts Of Interest ◽  
Dominant Negative ◽  
Zinc Finger Domain

Abstract Abstract 3217 The zinc finger protein Erythroid Krüuppel-like factor (EKLF, KLF1) regulates definitive erythropoiesis and terminal differentiation of red blood cells. KLF1 facilitates transcription through high affinity binding to CACCC elements within its erythroid-specific target genes which include genes encoding erythrocyte membrane skeleton (EMS) proteins. Deficiencies of EMS proteins lead to the hemolytic anemia Hereditary Spherocytosis (HS). We have identified a new HS gene by studying the hemolytic anemia mouse mutant Nan (Neonatal Anemia). Here we report that a mutation, E339D, in the second zinc finger domain of KLF1 is responsible for HS in Nan mice. The causative nature of the E339D mutation was verified with an allelic test cross between Nan/+ and heterozygous Klf1+/− knockout mice. Homology modeling predicted Nan KLF1 binds CACCC elements more tightly, suggesting that Nan KLF1 is a competitive inhibitor of wild type KLF1. Competitive inhibition may help explain the apparent disconnect between the finding that Nan/+ heterozygous mice are anemic, whereas Klf1+/− heterozygous mice are normal and haplo-sufficient. This is the first direct association of a KLF1mutation with a disease in adult mammals. After examining a small population of HS patients, we also discovered one HS patient with a KLF1 mutation, which resulted in a significant amino acid substitution (T251I) in the activator/repressor domain, 28 amino acid residues upstream of the first zinc finger domain. This HS subject had no known mutations in the exons or intron/exon boundaries of EMS genes (SPTA1, SPTB, ANK1, SLC4A1) which comprise 85% of HS mutations in humans. The lack of a known genetic mutation in EMS genes leaves this patient's KLF1 mutation as the leading candidate defect. The identification of the gene causing the Nan mutation is significant because the Nan mutant has allowed discovery of a new HS gene which may also cause this disease in humans. In addition, the putative dominant/negative competitive inhibition of the Nan mutation makes the Nan mouse an excellent model system to study the function of KLF1. Disclosures: No relevant conflicts of interest to declare.

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