scholarly journals Promyelocytic leukemia nuclear body (PML-NB) -free intranuclear milieu facilitates development of oocytes in mice

2021 ◽  
Author(s):  
Osamu Udagawa ◽  
Ayaka Kato-Udagawa ◽  
Seishiro Hirano
Keyword(s):  
Multiple Stressors ◽  
Liquid Droplet ◽  
Biological Activities ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Oocyte Nucleus ◽  
Oocyte Growth ◽  
Nuclear Maturation ◽  
Pml Nuclear Bodies

Promyelocytic leukemia (PML) nuclear bodies (PML-NBs), a class of membrane-less organelles in cells, are involved in multiple biological activities and are present throughout cells of adult organisms. Although the oocyte nucleus is an active region for the flux of multiple non-membranous organelles, PML-NBs have been predicted to be absent from oocytes. Here, we show that the deliberate assembly of PML-NBs during oocyte growth preferentially sequestered Small Ubiquitin-related Modifier (SUMO) protein from the nucleoplasm. SUMO not only was involved in the regulation of oocyte nuclear maturation but also was committed to the response, mediated by liquid droplet formation, to multiple stressors including nucleolar stress and proteotoxic stresses. Exogenous assembly of PML-NBs in the nucleus of oocytes affected the efficiency of the response of SUMO. These observations suggest that the PML-NB-free intranuclear milieu ensures that a reserve of SUMO remains available for emergent responses in oocyte development. This work demonstrated a benefit of the PML-NB-free intranuclear milieu, namely the ability to redirect the flux of SUMO otherwise needed to control PML-NB dynamics.

scholarly journals Arsenic-Induced SUMO-Dependent Recruitment of RNF4 into PML Nuclear Bodies

2010 ◽  
Vol 21 (23) ◽  
pp. 4227-4239 ◽  
Author(s):  
Marie-Claude Geoffroy ◽  
Ellis G. Jaffray ◽  
Katherine J. Walker ◽  
Ronald T. Hay
Keyword(s):  
Retinoic Acid Receptor ◽  
E3 Ligase ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Dependent Manner ◽  
Nuclear Trafficking ◽  
Sumo Modification ◽  
Ubiquitin E3 Ligase ◽  
Pml Nuclear Bodies

In acute promyelocytic leukemia (APL), the promyelocytic leukemia (PML) protein is fused to the retinoic acid receptor alpha (RAR). Arsenic is an effective treatment for this disease as it induces SUMO-dependent ubiquitin-mediated proteasomal degradation of the PML-RAR fusion protein. Here we analyze the nuclear trafficking dynamics of PML and its SUMO-dependent ubiquitin E3 ligase, RNF4 in response to arsenic. After administration of arsenic, PML immediately transits into nuclear bodies where it undergoes SUMO modification. This initial recruitment of PML into nuclear bodies is not dependent on RNF4, but RNF4 quickly follows PML into the nuclear bodies where it is responsible for ubiquitylation of SUMO-modified PML and its degradation by the proteasome. While arsenic restricts the mobility of PML, FRAP analysis indicates that RNF4 continues to rapidly shuttle into PML nuclear bodies in a SUMO-dependent manner. Under these conditions FRET studies indicate that RNF4 interacts with SUMO in PML bodies but not directly with PML. These studies indicate that arsenic induces the rapid reorganization of the cell nucleus by SUMO modification of nuclear body-associated PML and uptake of the ubiquitin E3 ligase RNF4 leading to the ubiquitin-mediated degradation of PML.

scholarly journals Role of Promyelocytic Leukemia (Pml) Sumolation in Nuclear Body Formation, 11s Proteasome Recruitment, and as2O3-Induced Pml or Pml/Retinoic Acid Receptor α Degradation

2001 ◽  
Vol 193 (12) ◽  
pp. 1361-1372 ◽  
Author(s):  
Valérie Lallemand-Breitenbach ◽  
Jun Zhu ◽  
Francine Puvion ◽  
Marcel Koken ◽  
Nicole Honoré ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Nuclear Matrix ◽  
Viral Infections ◽  
Retinoic Acid Receptor ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Acid Receptor ◽  
Pml Nuclear Bodies ◽  
Retinoic Acid Receptor Α

Promyelocytic leukemia (PML) is the organizer of nuclear matrix domains, PML nuclear bodies (NBs), with a proposed role in apoptosis control. In acute promyelocytic leukemia, PML/retinoic acid receptor (RAR) α expression disrupts NBs, but therapies such as retinoic acid or arsenic trioxide (As2O3) restore them. PML is conjugated by the ubiquitin-related peptide SUMO-1, a process enhanced by As2O3 and proposed to target PML to the nuclear matrix. We demonstrate that As2O3 triggers the proteasome-dependent degradation of PML and PML/RARα and that this process requires a specific sumolation site in PML, K160. PML sumolation is dispensable for its As2O3-induced matrix targeting and formation of primary nuclear aggregates, but is required for the formation of secondary shell-like NBs. Interestingly, only these mature NBs harbor 11S proteasome components, which are further recruited upon As2O3 exposure. Proteasome recruitment by sumolated PML only likely accounts for the failure of PML-K160R to be degraded. Therefore, studying the basis of As2O3-induced PML/RARα degradation we show that PML sumolation directly or indirectly promotes its catabolism, suggesting that mature NBs could be sites of intranuclear proteolysis and opening new insights into NB alterations found in viral infections or transformation.

scholarly journals Analysis of Autoantibodies against Promyelocytic Leukemia Nuclear Body Components and Biochemical Parameters in Sera of Patients with Primary Biliary Cholangitis

Diagnostics ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 587
Author(s):  
Alicja Bauer ◽  
Andrzej Habior ◽  
Paulina Wieszczy ◽  
Damian Gawel
Keyword(s):  
Alkaline Phosphatase ◽  
Histological Grade ◽  
High Specificity ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Primary Biliary Cholangitis ◽  
Serum Samples ◽  
Diagnostic Significance ◽  
Pml Nuclear Bodies

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by immune-mediated destruction of intrahepatic bile ducts and the presence of specific antibodies. The aim of the study was to examine the diagnostic significance of antibodies against promyelocytic leukemia nuclear body (PML NB) components such as Sp100, Sp140, and PML in a cohort of PBC patients and compare the results with biochemical and histological parameters. Serum samples were collected from 93 PBC patients. Anti-Sp100 and anti-PML antibodies were assessed using commercially available kits, anti-Sp140 using developed “in-house” ELISA test. Anti-Sp140, anti-Sp100, and anti-PML antibodies were present in 25 (27%), 37 (40%), and 29 (31%) PBC patients, respectively. Anti-PML NB positive patients also showed increased concentration of bilirubin and alkaline phosphatase (p < 0.05). In the group with the presence of at least two types of these antibodies, more frequent deaths or transplantations were observed. A correlation between the presence of antibodies and histological grade (OR = 2.55 p = 0.039) was established. Patients with bilirubin > 1.1 mg/dL at the time of diagnosis had a significantly shorter time of survival than patients with bilirubin ≤ 1.1 mg/dL (HR 5.7; 95% C.I., 2.7, 12.3; p < 0.001). Our data confirm very high specificity of anti-PML NB antibodies, which can expand the laboratory diagnostic capabilities of PBC. We found an association between positive reactivity of autoantibodies directed against components of PML nuclear bodies and higher concentrations of bilirubin and alkaline phosphatase, but the main prognostic marker of survival remains serum bilirubin.

scholarly journals FLT3-ITD impedes retinoic acid, but not arsenic, responses in murine acute promyelocytic leukemias

Blood ◽  
2019 ◽  
Vol 133 (13) ◽  
pp. 1495-1506 ◽  
Author(s):  
Cécile Esnault ◽  
Ramy Rahmé ◽  
Kim L. Rice ◽  
Caroline Berthier ◽  
Coline Gaillard ◽  
...  
Keyword(s):  
Risk Factor ◽  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
P53 Signaling ◽  
Pml Nuclear Bodies ◽  
All Trans Retinoic Acid

Abstract Acute promyelocytic leukemia (APL) is often associated with activating FLT3 signaling mutations. These are highly related to hyperleukocytosis, a major adverse risk factor with chemotherapy-based regimens. APL is a model for oncogene-targeted therapies: all-trans retinoic acid (ATRA) and arsenic both target and degrade its ProMyelocytic Leukemia/Retinoic Acid Receptor α (PML/RARA) driver. The combined ATRA/arsenic regimen now cures virtually all patients with standard-risk APL. Although FLT3-internal tandem duplication (ITD) was an adverse risk factor for historical ATRA/chemotherapy regimens, the molecular bases for this effect remain unknown. Using mouse APL models, we unexpectedly demonstrate that FLT3-ITD severely blunts ATRA response. Remarkably, although the transcriptional output of initial ATRA response is unaffected, ATRA-induced PML/RARA degradation is blunted, as is PML nuclear body reformation and activation of P53 signaling. Critically, the combination of ATRA and arsenic fully rescues therapeutic response in FLT3-ITD APLs, restoring PML/RARA degradation, PML nuclear body reformation, P53 activation, and APL eradication. Moreover, arsenic targeting of normal PML also contributes to APL response in vivo. These unexpected results explain the less favorable outcome of FLT3-ITD APLs with ATRA-based regimens, and stress the key role of PML nuclear bodies in APL eradication by the ATRA/arsenic combination.

scholarly journals Promyelocytic Leukemia (Pml) Nuclear Bodies Are Protein Structures That Do Not Accumulate RNA

2000 ◽  
Vol 148 (2) ◽  
pp. 283-292 ◽  
Author(s):  
François-Michel Boisvert ◽  
Michael J. Hendzel ◽  
David P. Bazett-Jones
Keyword(s):  
Regulation Of Gene Expression ◽  
Protein Structures ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Electron Microscopic ◽  
The Core ◽  
Pml Nuclear Bodies ◽  
Nascent Rna ◽  
A Site

The promyelocytic leukemia (PML) nuclear body (also referred to as ND10, POD, and Kr body) is involved in oncogenesis and viral infection. This subnuclear domain has been reported to be rich in RNA and a site of nascent RNA synthesis, implicating its direct involvement in the regulation of gene expression. We used an analytical transmission electron microscopic method to determine the structure and composition of PML nuclear bodies and the surrounding nucleoplasm. Electron spectroscopic imaging (ESI) demonstrates that the core of the PML nuclear body is a dense, protein-based structure, 250 nm in diameter, which does not contain detectable nucleic acid. Although PML nuclear bodies contain neither chromatin nor nascent RNA, newly synthesized RNA is associated with the periphery of the PML nuclear body, and is found within the chromatin-depleted region of the nucleoplasm immediately surrounding the core of the PML nuclear body. We further show that the RNA does not accumulate in the protein core of the structure. Our results dismiss the hypothesis that the PML nuclear body is a site of transcription, but support the model in which the PML nuclear body may contribute to the formation of a favorable nuclear environment for the expression of specific genes.

scholarly journals The Transcription Coactivator Cbp Is a Dynamic Component of the Promyelocytic Leukemia Nuclear Body

2001 ◽  
Vol 152 (5) ◽  
pp. 1099-1106 ◽  
Author(s):  
François-Michel Boisvert ◽  
Michael J. Kruhlak ◽  
Alan K. Box ◽  
Michael J. Hendzel ◽  
David P. Bazett-Jones
Keyword(s):  
State Level ◽  
Camp Response Element Binding ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Dynamic Component ◽  
Pml Nuclear Bodies ◽  
Pml Bodies ◽  
Element Binding Protein ◽  
Transcription Coactivator

The transcription coactivator and histone acetyltransferase CAMP response element–binding protein (CBP) has been demonstrated to accumulate in promyelocytic leukemia (PML) bodies. We show that this accumulation is cell type specific. In cells where CBP does not normally accumulate in PML bodies, it can be induced to accumulate in PML bodies through overexpression of either CBP or Pml, but not Sp100. Using fluorescence recovery after photobleaching, we demonstrate that CBP moves rapidly into and out of PML bodies. In contrast, Pml and Sp100 are relatively immobile in the nucleoplasm and within PML nuclear bodies. They possess the characteristics expected of proteins that would play a structural role in the integrity of these subnuclear domains. Our results are consistent with CBP being a dynamic component of PML bodies and that the steady-state level in these structures can be modulated by Pml.

scholarly journals Nuclear body phase separation drives telomere clustering in ALT cancer cells

2020 ◽  
Vol 31 (18) ◽  
pp. 2048-2056 ◽  
Author(s):  
Huaiying Zhang ◽  
Rongwei Zhao ◽  
Jason Tones ◽  
Michel Liu ◽  
Robert L. Dilley ◽  
...  
Keyword(s):  
Dna Repair ◽  
Phase Separation ◽  
Cancer Cells ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Telomere Elongation ◽  
Alternative Lengthening ◽  
Induce Phase Separation ◽  
Induce Phase

A chemical dimerization approach is developed to induce phase separation of APB nuclear bodies involved in telomere elongation in alternative lengthening of telomeres (ALT) cancer cells. It reveals that ALT telomere-associated promyelocytic leukemia nuclear body (APB) fusion leads to telomere clustering to provide templates for homology-directed telomere synthesis, an ability that is decoupled from APB function in enriching DNA repair factors.

scholarly journals Adenovirus E1B 55-Kilodalton Protein Is a p53-SUMO1 E3 Ligase That Represses p53 and Stimulates Its Nuclear Export through Interactions with Promyelocytic Leukemia Nuclear Bodies

2010 ◽  
Vol 84 (23) ◽  
pp. 12210-12225 ◽  
Author(s):  
Mario A. Pennella ◽  
Yue Liu ◽  
Jennifer L. Woo ◽  
Chongwoo A. Kim ◽  
Arnold J. Berk
Keyword(s):  
Nuclear Export ◽  
P53 Mutation ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Live Cells ◽  
High Concentration ◽  
Sumoylation Site ◽  
Pml Nuclear Bodies ◽  
Induced Apoptosis

ABSTRACT Oncogenic transformation by adenovirus E1A and E1B-55K requires E1B-55K inhibition of p53 activity to prevent E1A-induced apoptosis. During viral infection, E1B-55K and E4orf6 substitute for the substrate-binding subunits of the host cell cullin 5 class of ubiquitin ligases, resulting in p53 polyubiquitinylation and proteasomal degradation. Here we show that E1B-55K alone also functions as an E3 SUMO1-p53 ligase. Fluorescence microscopy studies showed that E1B-55K alone, in the absence of other viral proteins, causes p53 to colocalize with E1B-55K in promyelocytic leukemia (PML) nuclear bodies, nuclear domains with a high concentration of sumoylated proteins. Photobleaching experiments with live cells revealed that E1B-55K tethering of p53 in PML nuclear bodies decreases the in vivo nuclear mobility of p53 nearly 2 orders of magnitude. E1B-55K-induced p53 sumoylation contributes to maximal inhibition of p53 function since mutation of the major p53 sumoylation site decreases E1B-55K-induced p53 sumoylation, tethering in PML nuclear bodies, and E1B-55K inhibition of p53 activity. Mutation of the E1B-55K sumoylation site greatly inhibits E1B-55K association with PML nuclear bodies and the p53 nuclear export to cytoplasmic aggresomes observed in E1A-E1B-transformed cells. Purified E1B-55K and p53 form high-molecular-weight complexes potentially through the formation of a network of E1B-55K dimers bound to the N termini of p53 tetramers. In support of this model, a p53 mutation that prevents tetramer formation greatly reduces E1B-55K-induced tethering in PML nuclear bodies and p53 nuclear export. These data indicate that E1B-55K's association with PML nuclear bodies inactivates p53 by first sequestering it in PML nuclear bodies and then greatly facilitating its nuclear export.

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