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1.
Mol Syst Biol ; 20(4): 374-402, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38459198

RESUMEN

Sex-based differences in obesity-related hepatic malignancies suggest the protective roles of estrogen. Using a preclinical model, we dissected estrogen receptor (ER) isoform-driven molecular responses in high-fat diet (HFD)-induced liver diseases of male and female mice treated with or without an estrogen agonist by integrating liver multi-omics data. We found that selective ER activation recovers HFD-induced molecular and physiological liver phenotypes. HFD and systemic ER activation altered core liver pathways, beyond lipid metabolism, that are consistent between mice and primates. By including patient cohort data, we uncovered that ER-regulated enhancers govern central regulatory and metabolic genes with clinical significance in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including the transcription factor TEAD1. TEAD1 expression increased in MASLD patients, and its downregulation by short interfering RNA reduced intracellular lipid content. Subsequent TEAD small molecule inhibition improved steatosis in primary human hepatocyte spheroids by suppressing lipogenic pathways. Thus, TEAD1 emerged as a new therapeutic candidate whose inhibition ameliorates hepatic steatosis.


Asunto(s)
Hígado Graso , Enfermedad del Hígado Graso no Alcohólico , Animales , Femenino , Humanos , Masculino , Ratones , Dieta Alta en Grasa/efectos adversos , Estrógenos , Hígado Graso/genética , Hígado Graso/metabolismo , Expresión Génica , Hígado/metabolismo , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/uso terapéutico , Factores de Transcripción de Dominio TEA
2.
Kidney Int ; 105(6): 1200-1211, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38423183

RESUMEN

Podocyte injury and loss are hallmarks of diabetic nephropathy (DN). However, the molecular mechanisms underlying these phenomena remain poorly understood. YAP (Yes-associated protein) is an important transcriptional coactivator that binds with various other transcription factors, including the TEAD family members (nuclear effectors of the Hippo pathway), that regulate cell proliferation, differentiation, and apoptosis. The present study found an increase in YAP phosphorylation at S127 of YAP and a reduction of nuclear YAP localization in podocytes of diabetic mouse and human kidneys, suggesting dysregulation of YAP may play a role in diabetic podocyte injury. Tamoxifen-inducible podocyte-specific Yap gene knockout mice (YappodKO) exhibited accelerated and worsened diabetic kidney injury. YAP inactivation decreased transcription factor WT1 expression with subsequent reduction of Tead1 and other well-known targets of WT1 in diabetic podocytes. Thus, our study not only sheds light on the pathophysiological roles of the Hippo pathway in diabetic podocyte injury but may also lead to the development of new therapeutic strategies to prevent and/or treat DN by targeting the Hippo signaling pathway.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Diabetes Mellitus Experimental , Nefropatías Diabéticas , Ratones Noqueados , Fosfoproteínas , Podocitos , Transducción de Señal , Factores de Transcripción , Proteínas WT1 , Proteínas Señalizadoras YAP , Podocitos/metabolismo , Podocitos/patología , Animales , Proteínas WT1/metabolismo , Proteínas WT1/genética , Proteínas Señalizadoras YAP/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/genética , Humanos , Fosforilación , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaciones , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Factores de Transcripción de Dominio TEA/metabolismo , Vía de Señalización Hippo , Ratones , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Masculino , Ratones Endogámicos C57BL , Tamoxifeno/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética
3.
Biochem Biophys Res Commun ; 718: 150037, 2024 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-38735135

RESUMEN

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for more than 80 % of lung cancer (LC) cases, making it the primary cause of cancer-related mortality worldwide. T-box transcription factor 5 (TBX5) is an important regulator of embryonic and organ development and plays a key role in cancer development. Here, our objective was to investigate the involvement of TBX5 in ferroptosis within LC cells and the underlying mechanisms. METHODS: First, TBX5 expression was examined in human LC cells. Next, overexpression of TBX5 and Yes1-associated transcriptional regulator (YAP1) and knockdown of TEA domain 1 (TEAD1) were performed in A549 and NCI-H1703 cells. The proliferation ability of A549 and NCI-H1703 cells, GSH, MDA, ROS, and Fe2+ levels were measured. Co-immunoprecipitation (Co-IP) was performed to verify whether TBX5 protein could bind YAP1. Then TBX5, YAP1, TEAD1, GPX4, p53, FTH1, SLC7A11 and PTGS2 protein levels were assessed. Finally, we verified the effect of TBX5 on ferroptosis in LC cells in vivo. RESULTS: TBX5 expression was down-regulated in LC cells, especially in A549 and NCI-H1703 cells. Overexpression of TBX5 significantly decreased proliferation ability of A549 and NCI-H1703 cells, downregulated GPX4 and GSH levels, and upregulated MDA, ROS, and Fe2+ levels. Co-IP verified that TBX5 protein could bind YAP1. Moreover, oe-YAP1 promoted proliferation ability of A549 and NCI-H1703 cells transfected with Lv-TBX5, upregulated GPX4 and GSH levels and downregulated MDA, ROS, and Fe2+ levels. Additionally, oe-YAP1 promoted FTH1 and SLC7A11 levels and inhibited p53 and PTGS2 levels in A549 and NCI-H1703 cells transfected with Lv-TBX5. However, transfection with si-TEAD1 further reversed these effects. In vivo experiments further validated that TBX5 promoted ferroptosis in LC cells. CONCLUSIONS: TBX5 inhibited the activation of YAP1-TEAD1 pathway to promote ferroptosis in LC cells.


Asunto(s)
Ferroptosis , Neoplasias Pulmonares , Proteínas de Dominio T Box , Factores de Transcripción de Dominio TEA , Factores de Transcripción , Proteínas Señalizadoras YAP , Ferroptosis/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factores de Transcripción de Dominio TEA/metabolismo , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Animales , Línea Celular Tumoral , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Ratones Desnudos , Proliferación Celular , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Ratones , Regulación Neoplásica de la Expresión Génica , Células A549 , Transducción de Señal , Especies Reactivas de Oxígeno/metabolismo
4.
J Virol ; 97(8): e0081523, 2023 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-37578237

RESUMEN

Transcription of the human papillomavirus (HPV) oncogenes, E6 and E7, is regulated by the long control region (LCR) of the viral genome. Although various transcription factors have been reported to bind to the LCR, little is known about the transcriptional cofactors that modulate HPV oncogene expression in association with these transcription factors. Here, we performed in vitro DNA-pulldown purification of nuclear proteins in cervical cancer cells, followed by proteomic analyses to identify transcriptional cofactors that bind to the HPV16 LCR via the transcription factor TEAD1. We detected the proinflammatory cytokine S100A9 that localized to the nucleus of cervical cancer cells and associated with the LCR via direct interaction with TEAD1. Nuclear S100A9 levels and its association with the LCR were increased in cervical cancer cells by treatment with a proinflammatory phorbol ester. Knockdown of S100A9 decreased HPV oncogene expression and reduced the growth of cervical cancer cells and their susceptibility to cisplatin, whereas forced nuclear expression of S100A9 using nuclear localization signals exerted opposite effects. Thus, we conclude that nuclear S100A9 binds to the HPV LCR via TEAD1 and enhances viral oncogene expression by acting as a transcriptional coactivator. IMPORTANCE Human papillomavirus (HPV) infection is the primary cause of cervical cancer, and the viral oncogenes E6 and E7 play crucial roles in carcinogenesis. Although cervical inflammation contributes to the development of cervical cancer, the molecular mechanisms underlying the role of these inflammatory responses in HPV carcinogenesis are not fully understood. Our study shows that S100A9, a proinflammatory cytokine, is induced in the nucleus of cervical cancer cells by inflammatory stimuli, and it enhances HPV oncogene expression by acting as a transcriptional coactivator of TEAD1. These findings provide new molecular insights into the relationship between inflammation and viral carcinogenesis.


Asunto(s)
Calgranulina B , Proteínas Oncogénicas Virales , Infecciones por Papillomavirus , Factores de Transcripción de Dominio TEA , Neoplasias del Cuello Uterino , Femenino , Humanos , Carcinogénesis/genética , Virus del Papiloma Humano , Proteínas Oncogénicas Virales/genética , Proteínas E7 de Papillomavirus/genética , Infecciones por Papillomavirus/genética , Proteómica , Factores de Transcripción de Dominio TEA/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/virología , Calgranulina B/genética
5.
Cell Biol Toxicol ; 40(1): 30, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38740637

RESUMEN

In pancreatic ductal adenocarcinomas (PDAC), profound hypoxia plays key roles in regulating cancer cell behavior, including proliferation, migration, and resistance to therapies. The initial part of this research highlights the important role played by long noncoding RNA (lncRNA) MKLN1-AS, which is controlled by hypoxia-inducible factor-1 alpha (HIF-1α), in the progression of PDAC. Human samples of PDAC showed a notable increase in MKLN1-AS expression, which was linked to a worse outcome. Forced expression of MKLN1-AS greatly reduced the inhibitory impact on the growth and spread of PDAC cells caused by HIF-1α depletion. Experiments on mechanisms showed that HIF-1α influences the expression of MKLN1-AS by directly attaching to a hypoxia response element in the promoter region of MKLN1-AS.MKLN1-AS acts as a competitive endogenous RNA (ceRNA) by binding to miR-185-5p, resulting in the regulation of TEAD1 expression and promoting cell proliferation, migration, and tumor growth. TEAD1 subsequently enhances the development of PDAC. Our study results suggest that MKLN1-AS could serve as a promising target for treatment and a valuable indicator for predicting outcomes in PDAC. PDAC is associated with low oxygen levels, and the long non-coding RNA MKLN1-AS interacts with TEAD1 in this context.


Asunto(s)
Carcinoma Ductal Pancreático , Movimiento Celular , Proliferación Celular , Proteínas de Unión al ADN , Regulación Neoplásica de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia , MicroARNs , Neoplasias Pancreáticas , ARN Largo no Codificante , Factores de Transcripción de Dominio TEA , Animales , Humanos , Ratones , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Transducción de Señal/genética , Factores de Transcripción de Dominio TEA/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética
6.
Bioorg Chem ; 145: 107208, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38354501

RESUMEN

Hepatocellular carcinoma (HCC) is a major challenge for human healthy. Daphnane-type diterpenes have attracted increasingly attention due to remarkable pharmaceutical potential including anti-HCC activity. To further develop this class of compounds as inhibitors of HCC, the daphnane diterpenoids 12-O-debenzoyl-Yuanhuacine (YHC) and 12-hydroxydaphnetoxin (YHE) were prepared by a standard chemical transformation from dried flower buds of the Daphne genkwa plant. Subsequently, 22 daphnane diterpenoidal 1,3,4-oxdiazole derivatives were rationally designed and synthesized based on YHC and YHE. The assessment of the target compound's anti-hepatocellular carcinoma activity revealed that YHC1 exhibited comparable activity to sorafenib in the Hep3B cell line, while demonstrating higher selectivity. The mechanistic investigation demonstrates that compound YHC1 induces cell cycle arrest at the G0/G1 phase, cellular senescence, apoptosis, and elevates cellular reactive oxygen species levels. Moreover, molecular docking and CETSA results confirm the interaction between YHC1 and YAP1 as well as TEAD1. Co-IP experiments further validated that YHC1 can effectively inhibit the binding of YAP1 and TEAD1. In conclusion, YHC1 selectively targets YAP1 and TEAD1, exhibiting its anti-hepatocellular carcinoma effects through the inhibition of their interaction.


Asunto(s)
Carcinoma Hepatocelular , Daphne , Diterpenos , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Daphne/química , Diterpenos/farmacología , Diterpenos/química , Neoplasias Hepáticas/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Oxadiazoles/química , Oxadiazoles/farmacología
7.
Cell Mol Life Sci ; 80(8): 215, 2023 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-37468661

RESUMEN

BACKGROUND: We have shown that Hippo-YAP signaling pathway plays an important role in endothelial cell differentiation. Vestigial-like family member 4 (VGLL4) has been identified as a YAP inhibitor. However, the exact function of VGLL4 in vascular endothelial cell development remains unclear. In this study, we investigated the role of VGLL4, in human endothelial lineage specification both in 3D vascular organoid and 2D endothelial cell differentiation. METHODS AND RESULTS: In this study, we found that VGLL4 was increased during 3D vascular organoids generation and directed differentiation of human embryonic stem cells H1 towards the endothelial lineage. Using inducible ectopic expression of VGLL4 based on the piggyBac system, we proved that overexpression of VGLL4 in H1 promoted vascular organoids generation and endothelial cells differentiation. In contrast, VGLL4 knockdown (heterozygous knockout) of H1 exhibited inhibitory effects. Using bioinformatics analysis and protein immunoprecipitation, we further found that VGLL4 binds to TEAD1 and facilitates the expression of endothelial master transcription factors, including FLI1, to promote endothelial lineage specification. Moreover, TEAD1 overexpression rescued VGLL4 knockdown-mediated negative effects. CONCLUSIONS: In summary, VGLL4 promotes EC lineage specification both in 3D vascular organoid and 2D EC differentiation from pluripotent stem cell, VGLL4 interacts with TEAD1 and facilitates EC key transcription factor, including FLI1, to enhance EC lineage specification.


Asunto(s)
Células Endoteliales , Células Madre Pluripotentes , Humanos , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Factores de Transcripción/metabolismo , Regulación de la Expresión Génica , Diferenciación Celular , Células Madre Pluripotentes/metabolismo , Factores de Transcripción de Dominio TEA
8.
Adv Exp Med Biol ; 1441: 295-311, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38884718

RESUMEN

Cardiac development is a fine-tuned process governed by complex transcriptional networks, in which transcription factors (TFs) interact with other regulatory layers. In this chapter, we introduce the core cardiac TFs including Gata, Hand, Nkx2, Mef2, Srf, and Tbx. These factors regulate each other's expression and can also act in a combinatorial manner on their downstream targets. Their disruption leads to various cardiac phenotypes in mice, and mutations in humans have been associated with congenital heart defects. In the second part of the chapter, we discuss different levels of regulation including cis-regulatory elements, chromatin structure, and microRNAs, which can interact with transcription factors, modulate their function, or are downstream targets. Finally, examples of disturbances of the cardiac regulatory network leading to congenital heart diseases in human are provided.


Asunto(s)
Redes Reguladoras de Genes , Cardiopatías Congénitas , Factores de Transcripción , Animales , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/metabolismo , Regulación del Desarrollo de la Expresión Génica , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Corazón/fisiología , Miocardio/metabolismo
9.
J Mol Cell Cardiol ; 176: 21-32, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36657637

RESUMEN

The Hippo signaling pathway plays a critical role in cardiovascular development and stem cell differentiation. Using microarray profiling, we found that the Hippo pathway components vestigial-like family member 4 (VGLL4) and TEA domain transcription factor 1 (TEAD1) were upregulated during vascular smooth muscle cell (VSMC) differentiation from H1 ESCs (H1 embryonic stem cells). To further explore the role and molecular mechanisms of VGLL4 in regulating VSMC differentiation, we generated a VGLL4-knockdown H1 ESC line (heterozygous knockout) using the CRISPR/Cas9 system and found that VGLL4 knockdown inhibited VSMC specification. In contrast, overexpression of VGLL4 using the PiggyBac transposon system facilitated VSMC differentiation. We confirmed that this effect was mediated via TEAD1 and VGLL4 interaction. In addition, bioinformatics analysis revealed that Ten-eleven-translocation 2 (TET2), a DNA dioxygenase, is a target of TEAD1, and a luciferase assay further verified that TET2 is the target of the VGLL4-TEAD1 complex. Indeed, TET2 overexpression promoted VSMC marker gene expression and countered the VGLL4 knockdown-mediated inhibitory effects on VSMC differentiation. In summary, we revealed a novel role of VGLL4 in promoting VSMC differentiation from hESCs and identified TET2 as a new target of the VGLL4-TEAD1 complex, which may demethylate VSMC marker genes and facilitate VSMC differentiation. This study provides new insights into the VGLL4-TEAD1-TET2 axis in VSMC differentiation and vascular development.


Asunto(s)
Dioxigenasas , Células Madre Pluripotentes , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Factores de Transcripción de Dominio TEA , Músculo Liso Vascular/metabolismo , Diferenciación Celular/fisiología , Células Madre Pluripotentes/metabolismo , Miocitos del Músculo Liso/metabolismo , Proliferación Celular
10.
Acta Biochim Biophys Sin (Shanghai) ; 55(10): 1592-1605, 2023 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-37723874

RESUMEN

AP000695.2 is a novel long non-coding RNA (lncRNA). Its aberrant high expression is remarkably associated with poor prognosis of patients with lung adenocarcinoma (LUAD). However, its role and underlying mechanism in LUAD remains unclear. Previous bioinformatics analysis indicated that AP000695.2 may be closely related to the glycolysis of LUAD. This study aims to verify and explore the mechanism of AP000695.2 in glycolysis of LUAD. Overexpression plasmid and siRNA are used to construct cell models of upregulation and downregulation of AP000695.2, respectively. AP000695.2 is highly expressed in lung cancer cell lines as revealed by qPCR. Western blot analysis, FDG uptake, lactate production assay and ECAR determination results show that high expression of AP000695.2 facilitates glycolysis of LUAD cells. CCK-8, EdU staining, Transwell and wound healing assays show that high expression of AP000695.2 promotes cell growth and migration of LUAD. The relationship between AP000695.2 and miR-335-3p is confirmed by bioinformatics analysis and dual-luciferase reporter assays. Through the dual-luciferase reporter assay, TEA domain transcription factor 1 (TEAD1) is identified as a target gene of miR-335-3p. Rescue experiments are applied to verify the relationship among AP000695.2, miR-335-3p and TEAD1. Our study indicates that AP000695.2 is involved in the mechanism of LUAD through functioning as a ceRNA to competitively sponge miR-335-3p, thereby regulating the expression of TEAD1. In the in vivo models, AP000695.2 depletion restrains tumor growth and glycolysis. AP000695.2 promotes the glycolysis of LUAD by regulating the miR-335-3p/TEAD1 axis, and it may serve as a potential target of anti-tumor energy metabolism therapy.


Asunto(s)
Adenocarcinoma , Neoplasias Pulmonares , MicroARNs , ARN Largo no Codificante , Humanos , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias Pulmonares/patología , Glucólisis/genética , Pulmón/metabolismo , Adenocarcinoma/patología , Luciferasas/metabolismo , Proliferación Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción de Dominio TEA
11.
Anim Biotechnol ; 34(8): 3589-3598, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36866843

RESUMEN

TEA domain transcription factor 1 (TEAD1), also called TEF-1, acts as a transcriptional enhancer to regulate muscle-specific gene expression. However, the role of TEAD1 in regulating intramuscular preadipocyte differentiation in goats is unclear. The aim of this study was to obtain the sequence of TEAD1 gene and elucidate the effect of TEAD1 on goat intramuscular preadipocyte differentiation in vitro and its possible mechanism. The results showed that the goat TEAD1 gene CDS region sequence was 1311 bp. TEAD1 gene was widely expressed in goat tissues, with the highest expression in brachial triceps (p < 0.01). The expression of TEAD1 gene in goat intramuscular adipocytes at 72 h was extremely significantly higher than that at 0 h (p < 0.01). Overexpression of goat TEAD1 inhibited the accumulation of lipid droplets in goat intramuscular adipocyte. The relative expression of differentiation marker genes SREBP1, PPARγ, C/EBPß were significantly down-regulated (all p < 0.01), but PREF-1 was significantly up-regulated (p < 0.01). Binding analysis showed that there were multiple binding sites between the DNA binding domain of goat TEAD1 and the promoter binding region of SREBP1, PPARγ, C/EBPß and PREF-1. In conclusion, TEAD1 negatively regulates the differentiation of goat intramuscular preadipocytes.


Asunto(s)
Cabras , Factores de Transcripción de Dominio TEA , Animales , Cabras/fisiología , PPAR gamma/metabolismo , Adipocitos/fisiología , Músculo Esquelético/metabolismo , Diferenciación Celular/genética , Adipogénesis/genética
12.
Arch Gynecol Obstet ; 307(6): 1795-1809, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-35708783

RESUMEN

PURPOSE: Events in the uterus during the peri-implantation period include embryo development, acquisition of uterine receptivity, implantation and decidualization. Hippo signaling pathway regulates cell proliferation, apoptosis and differentiation. We aimed to determine localization and expressions of pYAP (Phospho Yes-associated protein), YAP (Yes-associated protein), TEAD1 (TEA domain family member 1) and CTGF (Connective tissue growth factor), members of the Hippo signaling pathway, in the mouse uterus during the peri-implantation period. METHODS: Pregnant mice were randomly separated into 5 groups: 1st, 4th, 5th, 6th, and 8th days of pregnancy groups. Non-pregnant female mice in estrous phase were included in the estrous group. Uteri and implantation sites were collected. Also, inter-implantation sites were collected from the 5th day of pregnancy group. pYAP, YAP, TEAD-1 and CTGF were detected by immunohistochemistry and Western blotting. RESULTS: We observed that the expressions of YAP, TEAD-1 and CTGF were increased in the luminal and glandular epithelium on the 1st and 4th days of pregnancy when epithelial proliferation occurred. pYAP expression was high, and YAP and CTGF expressions were low in the luminal epithelium of the implantation sites on the 5th day of pregnancy, when epithelial differentiation occurred. pYAP expression was low, YAP and CTGF expressions were high at implantation sites on the 6th and 8th days of pregnancy, where decidua was formed. CONCLUSION: Our findings suggest that the Hippo signaling pathway might be involved in implantation and decidualization. Our findings will guide further studies and may help to elucidate underlying causes of implantation failure and pregnancy loss.


Asunto(s)
Vía de Señalización Hippo , Proteínas Señalizadoras YAP , Embarazo , Femenino , Ratones , Animales , Implantación del Embrión/fisiología , Útero/fisiología , Desarrollo Embrionario
13.
Exp Cell Res ; 404(2): 112664, 2021 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-34048786

RESUMEN

RNA methyltransferase NSUN2 is involved in cell proliferation and invasion in a variety of tumors. However, the expression, function, and mechanism of NSUN2 in hypopharyngeal squamous cell carcinoma (HPSCC) remains unknown. We used a bioinformatics database, polymerase chain reaction, cell culture and transfection, immunohistochemistry, cell proliferation assay, wound healing experiments, transwell assays, western blotting, RNA-seq detection, dual-luciferase reporter assay, in vivo experiments, and a dot blot assay to evaluate the role of NSUN2 in HPSCC. NSUN2 mRNA and protein were highly expressed in HPSCC; NSUN2 knockdown in vitro and in vivo decreased cell proliferation and invasion. Studies have shown that TEAD1, a transcription factor, may act downstream of NSUN2 in HPSCC. NSUN2 was found to promote the proliferation and invasion of HPSCC by upregulating TEAD1 in an 5-methylcytosine-dependent manner, thereby representing an oncogene and potential new target for treating HPSCC.


Asunto(s)
Proliferación Celular/genética , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Metiltransferasas/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Neoplasias de Cabeza y Cuello/genética , Humanos , Metiltransferasas/genética , Proteínas Nucleares/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Factores de Transcripción de Dominio TEA , Factores de Transcripción/genética
14.
J Mol Cell Cardiol ; 150: 54-64, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33045251

RESUMEN

AIMS: Calcific aortic valve disease (CAVD) is a primary cause of cardiovascular mortality; however, its mechanisms are unknown. Currently, no effective pharmacotherapy is available for CAVD. Aldo-keto reductase family 1 member B (Akr1B1) has been identified as a potential therapeutic target for valve interstitial cell calcification. Herein, we hypothesized that inhibition of Akr1B1 can attenuate aortic valve calcification. METHODS AND RESULTS: Normal and degenerative tricuspid calcific valves from human samples were analyzed by immunoblotting and immunohistochemistry. The results showed significant upregulation of Akr1B1 in CAVD leaflets. Akr1B1 inhibition attenuated calcification of aortic valve interstitial cells in osteogenic medium. In contrast, overexpression of Akr1B1 aggravated calcification in osteogenic medium. Mechanistically, using RNA sequencing (RNAseq), we revealed that Hippo-YAP signaling functions downstream of Akr1B1. Furthermore, we established that the protein level of the Hippo-YAP signaling effector active-YAP had a positive correlation with Akr1B1. Suppression of YAP reversed Akr1B1 overexpression-induced Runx2 upregulation. Moreover, YAP activated the Runx2 promoter through TEAD1 in a manner mediated by ChIP and luciferase reporter systems. Animal experiments showed that the Akr1B1 inhibitor epalrestat attenuated aortic valve calcification induced by a Western diet in LDLR-/- mice. CONCLUSION: This study demonstrates that inhibition of Akr1B1 can attenuate the degree of calcification both in vitro and in vivo. The Akr1B1 inhibitor epalrestat may be a potential treatment option for CAVD.


Asunto(s)
Aldehído Reductasa/metabolismo , Aldo-Ceto Reductasas/metabolismo , Estenosis de la Válvula Aórtica/enzimología , Estenosis de la Válvula Aórtica/patología , Válvula Aórtica/enzimología , Válvula Aórtica/patología , Calcinosis/enzimología , Calcinosis/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Aldehído Reductasa/antagonistas & inhibidores , Animales , Válvula Aórtica/efectos de los fármacos , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Inhibidores Enzimáticos/farmacología , Técnicas de Silenciamiento del Gen , Humanos , Lentivirus/metabolismo , Ratones , Osteogénesis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAP
15.
Biochem Biophys Res Commun ; 557: 85-89, 2021 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-33862464

RESUMEN

N6-methyladenosine (m6A) mRNA modification has been defined as a crucial regulator in various biological processes. Recent studies indicated an essential role of YTHDF1, an m6A reader, in the maintenance of intestinal stem cells (ISCs), while the detailed mechanism remains to be explored. By searching our m6A sequencing, RNA sequencing, and ribosome profiling data, we identified the transcriptional enhanced associate domain 1 (TEAD1) as a direct target of YTHDF1. We confirmed the presence of m6A modifications in TEAD1 mRNA and its binding with YTHDF1. Knockdown of either m6A methyltransferase METTL3 or YTHDF1 reduced the translation of TEAD1. TEAD1 was highly expressed in ISCs, while depletion of TEAD1 inhibited proliferation and induced differentiation of organoids. Overexpression of TEAD1 reversed the impaired stemness elicited by YTHDF1 depletion. These findings identify TEAD1 as a functional target of m6A-YTHDF1 in sustaining intestinal stemness.


Asunto(s)
Proteínas de Unión al ADN/biosíntesis , Intestinos/citología , Proteínas Nucleares/biosíntesis , Proteínas de Unión al ARN/metabolismo , Células Madre/citología , Células Madre/metabolismo , Factores de Transcripción/biosíntesis , Adenosina/análogos & derivados , Adenosina/genética , Adenosina/metabolismo , Animales , Línea Celular , Proliferación Celular/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células HCT116 , Humanos , Intestinos/fisiología , Metilación , Ratones , Ratones Noqueados , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Organoides , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Factores de Transcripción de Dominio TEA , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
16.
Exp Eye Res ; 207: 108575, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33864784

RESUMEN

Sveinsson's chorioretinal atrophy (SCRA) or helicoidal peripapillary chorioretinal degeneration (HPCD) as previously referred, is a rare ocular disease with autosomal dominant pattern of inheritance. The vast majority of reported cases were of Icelandic origin but the characteristic clinical picture of SCRA was also described in patients of non-Icelandic descent. Here, we report a novel disease-causing variant c.1261T>A, p.Tyr421Asn in TEAD1, detected in a Serbian family from Bosnia diagnosed with SCRA. The newly discovered change occurred at the same position as the "Icelandic mutation" (c.1261T>C, p.Tyr421His). According to our findings, this position in the exon 13 of the TEAD1 gene, at base pair 94, should be considered as a mutation hotspot and a starting point for future genetic analyses of patients with SCRA diagnosis.


Asunto(s)
Distrofias Hereditarias de la Córnea/genética , Proteínas de Unión al ADN/genética , Mutación Missense , Proteínas Nucleares/genética , Degeneración Retiniana/genética , Factores de Transcripción/genética , Población Blanca/genética , Adolescente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa , Serbia/epidemiología , Factores de Transcripción de Dominio TEA , Adulto Joven
17.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-34206257

RESUMEN

Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed. This study examined the expression pattern of Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, Tlr8, and Tlr9 in normal and disease-stressed mouse hearts. Our results demonstrated that the expression levels of cardiac Tlr3, Tlr7, Tlr8, and Tlr9 increased with age between neonatal and adult developmental stages, whereas the expression of Tlr5 decreased with age. Furthermore, pathological stress increased the expression levels of Tlr2, Tlr4, Tlr5, Tlr7, Tlr8, and Tlr9. Hippo-YAP signaling is essential for heart development and homeostasis maintenance, and YAP/TEAD1 complex is the terminal effector of this pathway. Here we found that TEAD1 directly bound genomic regions adjacent to Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, and Tlr9. In vitro, luciferase reporter data suggest that YAP/TEAD1 repression of Tlr4 depends on a conserved TEAD1 binding motif near Tlr4 transcription start site. In vivo, cardiomyocyte-specific YAP depletion increased the expression of most examined TLR genes, activated the synthesis of pro-inflammatory cytokines, and predisposed the heart to lipopolysaccharide stress. In conclusion, our data indicate that the expression of cardiac TLR genes is associated with age and activated by pathological stress and suggest that YAP/TEAD1 complex is a default repressor of cardiac TLR genes.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Unión al ADN/metabolismo , Inmunidad Innata , Miocitos Cardíacos/metabolismo , Receptores Toll-Like/genética , Factores de Transcripción/metabolismo , Factores de Edad , Animales , Citocinas/metabolismo , Regulación de la Expresión Génica , Lipopolisacáridos , Ratones , Ratones Endogámicos C57BL , Transducción de Señal , Factores de Transcripción de Dominio TEA , Proteínas Señalizadoras YAP
18.
Am J Physiol Heart Circ Physiol ; 319(1): H89-H99, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32502376

RESUMEN

Mitochondrial dysfunction occurs in most forms of heart failure. We have previously reported that Tead1, the transcriptional effector of Hippo pathway, is critical for maintaining adult cardiomyocyte function, and its deletion in adult heart results in lethal acute dilated cardiomyopathy. Growing lines of evidence indicate that Hippo pathway plays a role in regulating mitochondrial function, although its role in cardiomyocytes is unknown. Here, we show that Tead1 plays a critical role in regulating mitochondrial OXPHOS in cardiomyocytes. Assessment of mitochondrial bioenergetics in isolated mitochondria from adult hearts showed that loss of Tead1 led to a significant decrease in respiratory rates, with both palmitoylcarnitine and pyruvate/malate substrates, and was associated with reduced electron transport chain complex I activity and expression. Transcriptomic analysis from Tead1-knockout myocardium revealed genes encoding oxidative phosphorylation, TCA cycle, and fatty acid oxidation proteins as the top differentially enriched gene sets. Ex vivo loss of function of Tead1 in primary cardiomyocytes also showed diminished aerobic respiration and maximal mitochondrial oxygen consumption capacity, demonstrating that Tead1 regulation of OXPHOS in cardiomyocytes is cell autonomous. Taken together, our data demonstrate that Tead1 is a crucial transcriptional node that is a cell-autonomous regulator, a large network of mitochondrial function and biogenesis related genes essential for maintaining mitochondrial function and adult cardiomyocyte homeostasis.NEW & NOTEWORTHY Mitochondrial dysfunction constitutes an important aspect of heart failure etiopathogenesis and progression. However, the molecular mechanisms are still largely unknown. Growing lines of evidence indicate that Hippo-Tead pathway plays a role in cellular bioenergetics. This study reveals the novel role of Tead1, the downstream transcriptional effector of Hippo pathway, as a novel regulator of mitochondrial oxidative phosphorylation and in vivo cardiomyocyte energy metabolism, thus providing a potential therapeutic target for modulating mitochondrial function and enhancing cytoprotection of cardiomyocytes.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/metabolismo , Fosforilación Oxidativa , Factores de Transcripción/metabolismo , Animales , Respiración de la Célula , Células Cultivadas , Proteínas de Unión al ADN/genética , Complejo I de Transporte de Electrón/genética , Complejo I de Transporte de Electrón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción de Dominio TEA , Factores de Transcripción/genética , Transcriptoma
19.
Am J Respir Cell Mol Biol ; 60(1): 117-127, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30156429

RESUMEN

Angiogenesis, the formation of new blood capillaries, plays a key role in organ development and regeneration. Inhibition of lung angiogenesis through the blockade of angiogenic signaling pathways impairs compensatory and regenerative lung growth after unilateral pneumonectomy (PNX). The Hippo signaling transducer, Yes-associated protein (YAP) 1 binds to TEA domain transcription factor (TEAD) and controls organ size and regeneration. However, the role of endothelial YAP1 in lung vascular and alveolar morphogenesis remains unclear. In this report, we demonstrate that knockdown of YAP1 in endothelial cells (ECs) decreases angiogenic factor receptor Tie2 expression, and inhibits EC sprouting and epithelial cell budding in vitro and vascular and alveolar morphogenesis in the gel implanted on the mouse lung. The expression levels of YAP1, TEAD1, and Tie2 increase in ECs isolated from the remaining mouse lungs after unilateral PNX and vascular formation is stimulated in the post-PNX mouse lungs. Knockdown of endothelial YAP1 inhibits compensatory lung growth and vascular and alveolar morphogenesis after unilateral PNX. These findings suggest that endothelial YAP1 is required for lung vascular and alveolar regeneration and modulation of YAP1 in ECs may be novel interventions for the improvement of lung regeneration.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/fisiología , Angiopoyetinas/metabolismo , Pulmón/citología , Organogénesis , Fosfoproteínas/metabolismo , Fosfoproteínas/fisiología , Receptor TIE-2/metabolismo , Regeneración , Proteínas Adaptadoras Transductoras de Señales/genética , Angiopoyetinas/genética , Animales , Proteínas de Ciclo Celular , Proliferación Celular , Humanos , Pulmón/metabolismo , Ratones , Ratones Noqueados , Neovascularización Fisiológica , Fosfoproteínas/genética , Neumonectomía , Receptor TIE-2/genética , Transducción de Señal , Factores de Transcripción , Proteínas Señalizadoras YAP
20.
Development ; 143(17): 3128-42, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27578179

RESUMEN

Canonical Wnt/ß-catenin signaling plays an important role in myogenic differentiation, but its physiological role in muscle fibers remains elusive. Here, we studied activation of Wnt/ß-catenin signaling in adult muscle fibers and muscle stem cells in an Axin2 reporter mouse. Axin2 is a negative regulator and a target of Wnt/ß-catenin signaling. In adult muscle fibers, Wnt/ß-catenin signaling is only detectable in a subset of fast fibers that have a significantly smaller diameter than other fast fibers. In the same fibers, immunofluorescence staining for YAP/Taz and Tead1 was detected. Wnt/ß-catenin signaling was absent in quiescent and activated satellite cells. Upon injury, Wnt/ß-catenin signaling was detected in muscle fibers with centrally located nuclei. During differentiation of myoblasts expression of Axin2, but not of Axin1, increased together with Tead1 target gene expression. Furthermore, absence of Axin1 and Axin2 interfered with myoblast proliferation and myotube formation, respectively. Treatment with the canonical Wnt3a ligand also inhibited myotube formation. Wnt3a activated TOPflash and Tead1 reporter activity, whereas neither reporter was activated in the presence of Dkk1, an inhibitor of canonical Wnt signaling. We propose that Axin2-dependent Wnt/ß-catenin signaling is involved in myotube formation and, together with YAP/Taz/Tead1, associated with reduced muscle fiber diameter of a subset of fast fibers.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteína Axina/metabolismo , Proteínas de Unión al ADN/metabolismo , Fosfoproteínas/metabolismo , Factores de Transcripción/metabolismo , Vía de Señalización Wnt/fisiología , beta Catenina/metabolismo , Aciltransferasas , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteína Axina/genética , Proteínas de Ciclo Celular , Proteínas de Unión al ADN/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones , Desarrollo de Músculos/genética , Desarrollo de Músculos/fisiología , Fosfoproteínas/genética , Factores de Transcripción de Dominio TEA , Factores de Transcripción/genética , Vía de Señalización Wnt/genética , Proteína Wnt3A/genética , Proteína Wnt3A/metabolismo , Proteínas Señalizadoras YAP
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