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1.
J Cardiovasc Transl Res ; 16(5): 1232-1248, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37155136

RESUMO

Tamoxifen, a selective estrogen receptor modulator, was initially used to treat cancer in women and more recently to induce conditional gene editing in rodent hearts. However, little is known about the baseline biological effects of tamoxifen on the myocardium. In order to clarify the short-term effects of tamoxifen on cardiac electrophysiology of myocardium, we applied a single-chest-lead quantitative method and analyzed the short-term electrocardiographic phenotypes induced by tamoxifen in the heart of adult female mice. We found that tamoxifen prolonged the PP interval and caused a decreased heartbeat, and further induced atrioventricular block by gradually prolonging the PR interval. Further correlation analysis suggested that tamoxifen had a synergistic and dose-independent inhibition on the time course of the PP interval and PR interval. This prolongation of the critical time course may represent a tamoxifen-specific ECG excitatory-inhibitory mechanism, leading to a reduction in the number of supraventricular action potentials and thus bradycardia. Segmental reconstructions showed that tamoxifen induced a decrease in the conduction velocity of action potentials throughout the atria and parts of the ventricles, resulting in a flattening of the P wave and R wave. In addition, we detected the previously reported prolongation of the QT interval, which may be due to a prolonged duration of the ventricular repolarizing T wave rather than the depolarizing QRS complex. Our study highlights that tamoxifen can produce patterning alternations in the cardiac conduction system, including the formation of inhibitory electrical signals with reduced conduction velocity, implying its involvement in the regulation of myocardial ion transport and the mediation of arrhythmias. A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart(Figure 9). A working model of tamoxifen producing acute electrical disturbances in the myocardium. SN, sinus node; AVN, atrioventricular node; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.


Assuntos
Eletrocardiografia , Tamoxifeno , Humanos , Adulto , Feminino , Animais , Camundongos , Tamoxifeno/toxicidade , Arritmias Cardíacas , Sistema de Condução Cardíaco , Ventrículos do Coração , Nó Atrioventricular
2.
EMBO Rep ; 23(11): e54853, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36129789

RESUMO

Cohesin regulates sister chromatid cohesion but also contributes to chromosome folding by promoting the formation of chromatin loops, a process mediated by loop extrusion. Although PDS5 regulates cohesin dynamics on chromatin, the exact function of PDS5 in cohesin-mediated chromatin looping remains unclear. Two paralogs of PDS5 exist in vertebrates, PDS5A and PDS5B. Here we show that PDS5A and PDS5B co-localize with RAD21 and CTCF at loop anchors. Rapid PDS5A or PDS5B degradation in liver cancer cells using an inducible degron system reduces chromatin loops and increases loop size. RAD21 enrichment at loop anchors is decreased upon depletion of PDS5A or PDS5B. PDS5B loss also reduces CTCF signals at loop anchors and has a stronger effect on loop enlargement compared with PDS5A. Co-depletion of PDS5A and PDS5B reduces RAD21 levels at loop anchors although the amount of cohesin on chromatin is increased. Our study provides insight into how PDS5 proteins regulate cohesin-mediated chromatin looping.


Assuntos
Proteínas de Ciclo Celular , Proteínas Cromossômicas não Histona , Animais , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cromossomos/genética , Cromossomos/metabolismo , Cromatina/genética , Mamíferos/genética , Mamíferos/metabolismo , Coesinas
3.
Blood Adv ; 5(17): 3241-3253, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34448811

RESUMO

Epigenetic abnormalities are frequently involved in the initiation and progression of cancers, including acute myeloid leukemia (AML). A subtype of AML, acute promyelocytic leukemia (APL), is mainly driven by a specific oncogenic fusion event of promyelocytic leukemia-RA receptor fusion oncoprotein (PML-RARα). PML-RARα was reported as a transcription repressor through the interaction with nuclear receptor corepressor and histone deacetylase complexes leading to the mis-suppression of its target genes and differentiation blockage. Although previous studies were mainly focused on the connection of histone acetylation, it is still largely unknown whether alternative epigenetics mechanisms are involved in APL progression. KDM5A is a demethylase of histone H3 lysine 4 di- and tri-methylations (H3K4me2/3) and a transcription corepressor. Here, we found that the loss of KDM5A led to APL NB4 cell differentiation and retarded growth. Mechanistically, through epigenomics and transcriptomics analyses, KDM5A binding was detected in 1889 genes, with the majority of the binding events at promoter regions. KDM5A suppressed the expression of 621 genes, including 42 PML-RARα target genes, primarily by controlling the H3K4me2 in the promoters and 5' end intragenic regions. In addition, a recently reported pan-KDM5 inhibitor, CPI-455, on its own could phenocopy the differentiation effects as KDM5A loss in NB4 cells. CPI-455 treatment or KDM5A knockout could greatly sensitize NB4 cells to all-trans retinoic acid-induced differentiation. Our findings indicate that KDM5A contributed to the differentiation blockage in the APL cell line NB4, and inhibition of KDM5A could greatly potentiate NB4 differentiation.


Assuntos
Leucemia Promielocítica Aguda , Diferenciação Celular , Expressão Gênica , Humanos , Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteína 2 de Ligação ao Retinoblastoma
4.
Biochem Biophys Res Commun ; 533(4): 1212-1218, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33069358

RESUMO

The methylcytosine oxidase TET proteins play important roles in DNA demethylation and development. In developing embryos, TET2 are upregulated during pre-implantation development, and significantly expressed in the trophectoderm and inner cell mass. In this study, we identified Barx2 as a new target of Tet2. Tet2 bound and demethylated the promoter of Barx2 in mouse embryonic stem cells (mESCs) to maintain the expression of Barx2. During mESC differentiation, Tet2 bound the promoter of Barx2 in day 4 embryonic bodies but not in day 8 EBs. However, Barx2 expression remained unchanged. Thus, Tet2 functioned as a demethylase and maintained the expression of Barx2 in undifferentiated and early differentiated mESCs.


Assuntos
Diferenciação Celular/genética , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias/metabolismo , Proteínas de Homeodomínio/genética , Proteínas Proto-Oncogênicas/metabolismo , Animais , Células Cultivadas , Metilação de DNA , Proteínas de Ligação a DNA/genética , Dioxigenases , Células-Tronco Embrionárias/citologia , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/metabolismo , Camundongos , Regiões Promotoras Genéticas , Mapeamento de Interação de Proteínas , Proteínas Proto-Oncogênicas/genética
6.
Hepatology ; 61(5): 1603-14, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25557975

RESUMO

UNLABELLED: The prognosis for hepatocellular carcinoma (HCC) remains dismal in terms of overall survival (OS), and its molecular pathogenesis has not been completely defined. Here, we report that expression of deubiquitylase ubiquitin-specific protease 7 (USP7) is higher in human HCC tissues than in matched peritumoral tissues. Ectopic USP7 expression promotes growth of HCC cells in vivo and in vitro. Mechanistically, USP7 overexpression fosters HCC cell growth by forming a complex with and stabilizing thyroid hormone receptor-interacting protein 12 (TRIP12), which induces constitutive p14(ARF) ubiquitination. Clinically, USP7 overexpression is significantly correlated with a malignant phenotype, including larger tumor size, multiple tumor, poor differentiation, elevated alpha-fetoprotein, and microvascular invasion. Moreover, overexpression of USP7 and/or TRIP12 correlates with shorter OS and higher cumulative recurrence rates of HCC. CONCLUSION: USP7 stabilizes TRIP12 by deubiquitination, thus constitutively inactivating p14(ARF) and promoting HCC progression. This represents a novel marker for predicting prognosis and a potential therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias Hepáticas/metabolismo , Proteína Supressora de Tumor p14ARF/metabolismo , Ubiquitina Tiolesterase/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Peptidase 7 Específica de Ubiquitina
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