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1.
FASEB J ; 38(10): e23666, 2024 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-38780091

RESUMEN

Genome-wide association studies have identified many single nucleotide polymorphisms (SNPs) associated with erythrocyte traits. However, the functional variants and their working mechanisms remain largely unknown. Here, we reported that the SNP of rs80207740, which was associated with red blood cell (RBC) volume and hemoglobin content across populations, conferred enhancer activity to XPO7 gene via allele-differentially binding to Ikaros family zinc finger 1 (IKZF1). We showed that the region around rs80207740 was an erythroid-specific enhancer using reporter assays, and that the G-allele further enhanced activity. 3D genome evidence showed that the enhancer interacted with the XPO7 promoter, and eQTL analysis suggested that the G-allele upregulated expression of XPO7. We further showed that the rs80207740-G allele facilitated the binding of transcription factor IKZF1 in EMSA and ChIP analyses. Knockdown of IKZF1 and GATA1 resulted in decreased expression of Xpo7 in both human and mouse erythroid cells. Finally, we constructed Xpo7 knockout mouse by CRISPR/Cas9 and observed anemic phenotype with reduced volume and hemoglobin content of RBC, consistent to the effect of rs80207740 on erythrocyte traits. Overall, our study demonstrated that rs80207740 modulated erythroid indices by regulating IKZF1 binding and Xpo7 expression.


Asunto(s)
Alelos , Eritrocitos , Estudio de Asociación del Genoma Completo , Factor de Transcripción Ikaros , Polimorfismo de Nucleótido Simple , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , Humanos , Animales , Ratones , Eritrocitos/metabolismo , Carioferinas/genética , Carioferinas/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Regiones Promotoras Genéticas
2.
J Genet Genomics ; 51(6): 594-607, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38403115

RESUMEN

The post-transcriptional regulation of mRNA is a crucial component of gene expression. The disruption of this process has detrimental effects on the normal development and gives rise to various diseases. Searching for novel post-transcriptional regulators and exploring their roles are essential for understanding development and disease. Through a multimodal analysis of red blood cell trait genome-wide association studies (GWAS) and transcriptomes of erythropoiesis, we identify FAM46C, a non-canonical RNA poly(A) polymerase, as a necessary factor for proper red blood cell development. FAM46C is highly expressed in the late stages of the erythroid lineage, and its developmental upregulation is controlled by an erythroid-specific enhancer. We demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent manner. Furthermore, we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C, which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis. In conclusion, our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components, thereby promoting erythropoiesis.


Asunto(s)
Eritropoyesis , Polinucleotido Adenililtransferasa , Eritropoyesis/genética , Humanos , Animales , Ratones , Polinucleotido Adenililtransferasa/genética , Polinucleotido Adenililtransferasa/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estudio de Asociación del Genoma Completo , Mitocondrias/genética , Mitocondrias/metabolismo , Diferenciación Celular/genética , Lisosomas/metabolismo , Lisosomas/genética , Eritrocitos/metabolismo , Transcriptoma/genética
3.
Redox Biol ; 50: 102239, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35092867

RESUMEN

In ß-thalassemia, free α-globin chains are unstable and tend to aggregate or degrade, releasing toxic heme, porphyrins and iron, which produce reactive oxygen species (ROS). α-Hemoglobin-stabilizing protein (AHSP) is a potential modifier of ß-thalassemia due to its ability to escort free α-globin and inhibit the cellular production of ROS. The influence of AHSP on the redox equilibrium raises the question of whether AHSP expression is regulated by components of ROS signaling pathways and/or canonical redox proteins. Here, we report that AHSP expression in K562 cells could be stimulated by NFE2-related factor 2 (Nrf2) and its agonist tert-butylhydroquinone (tBHQ). This tBHQ-induced increase in AHSP expression was also observed in Ter119+ mouse erythroblasts at each individual stage during terminal erythroid differentiation. We further report that the AHSP level was elevated in α-globin-overexpressing K562 cells and staged erythroblasts from ßIVS-2-654 thalassemic mice. tBHQ treatment partially alleviated, whereas Nrf2 or AHSP knockdown exacerbated, α-globin precipitation and ROS production in fetal liver-derived thalassemic erythroid cells. MafG and Nrf2 occupancy at the MARE-1 site downstream of the AHSP transcription start site was detected in K562 cells. Finally, we show that MafG facilitated the activation of the AHSP gene in K562 cells by Nrf2. Our results demonstrate Nrf2-mediated feedback regulation of AHSP in response to excess α-globin, as occurs in ß-thalassemia.


Asunto(s)
Chaperonas Moleculares , Factor 2 Relacionado con NF-E2 , Talasemia beta , Animales , Proteínas Sanguíneas/metabolismo , Proteínas Portadoras/metabolismo , Ratones , Chaperonas Moleculares/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Talasemia beta/genética , Talasemia beta/metabolismo
4.
J Cell Mol Med ; 22(12): 6368-6379, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30334324

RESUMEN

Metformin (MET) is a diabetes drug that activates AMP-activated protein kinase (AMPK), and is suggested to have anticancer efficacy. Here, we investigated the role of AMPK signalling in prolactinoma (PRLoma), with particular respect to MET and bromocriptine (BC) as a PRLoma treatment. We analysed AMPK phosphorylation, dopamine D2 receptor (D2R), and oestrogen receptor (ER) expression in both BC-sensitive and -resistant PRLoma samples; effects of the AMPK agonist MET (alone or with BC) on in vitro proliferation and apoptosis, xenograft growth and prolactin (PRL) secretion of BC-sensitive and -resistant cells, and ER expression in xenografts. Some BC-resistant PRLomas showed high D2R expression but extremely low AMPK activation. MET significantly inhibited proliferation of cultured PRLoma cells; MET + BC notably restrained their PRL secretion. MET + BC further decreased tumour growth and serum PRL levels in xenografts than BC treatment alone. ER was down-regulated after AMPK activation in both cultured cells and xenografts. Together, we propose that the AMPK signalling pathway down-regulates ERα and ERß, and suppresses PRLoma growth as well as PRL secretion. Combined MET + BC is a potential treatment for PRLomas.


Asunto(s)
Metformina/administración & dosificación , Enfermedades de la Hipófisis/tratamiento farmacológico , Prolactinoma/tratamiento farmacológico , Proteínas Quinasas/genética , Receptores de Dopamina D2/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Apoptosis/efectos de los fármacos , Bromocriptina/administración & dosificación , Proliferación Celular/efectos de los fármacos , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Femenino , Xenoinjertos , Humanos , Ratones , Fosforilación/efectos de los fármacos , Enfermedades de la Hipófisis/genética , Enfermedades de la Hipófisis/patología , Prolactina/genética , Prolactinoma/genética , Prolactinoma/patología
5.
Cancer Lett ; 420: 60-71, 2018 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-29408653

RESUMEN

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide due to its chemoresistance and poor prognosis. Currently, there is a lack of effective small molecule drugs for the treatment of ESCC. Microtubules are an attractive target for cancer therapy since they play a central role in various fundamental cell functions. We investigated the anti-ESCC activity and mechanisms of the small molecule tubulin ligands, SL-3-19 and SL-1-73, which are two carbazole sulfonamide derivatives, in vitro and in vivo for the first time. These drugs were previously screened from a small molecule library with over 450 compounds and optimized for high aqueous solubility [1,2]. Here, we reveal the promising activities of these compounds against esophageal cancer. Mechanistically, both SL-3-19 and SL-1-73 inhibited ESCC cell growth by inducing cell apoptosis and arresting the cell cycle at G2/M phase in a dose-dependent manner. These drugs effectively inhibited microtubule assembly, greatly disrupted microtubule maturation by down-regulating acetylated α-tubulin, and significantly disrupted the vascular structure by obstructing the formation of capillary-like tubes in vitro. Consistent with their in vitro activities, SL-3-19 and SL-1-73 inhibited the growth of ESCC xenografts and inhibited the microvessel density in vivo. In summary, SL-3-19 and SL-1-73 are novel microtubule-destabilizing agents that have a potential antitumor effect on ESCC both in vitro and in vivo, and SL-3-19 had a higher activity than SL-1-73, with a low IC50 value and an observable antitumor activity in vivo. These results indicate that SL-3-19 may be a new therapeutic candidate for ESCC treatment.


Asunto(s)
Carbazoles/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Microtúbulos/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Sulfonamidas/administración & dosificación , Animales , Carbazoles/química , Carbazoles/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Tubulina (Proteína)/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Oncotarget ; 8(37): 61742-61760, 2017 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-28977901

RESUMEN

PURPOSE: Esophageal squamous cell carcinoma (ESCC) is a serious malignant tumor that affects human health. We analyzed the correlation between serum stathmin level and ESCC and elucidated the molecular mechanisms of stathmin's promotion of ESCC cell invasion and metastasis. METHODS: Stathmin level in ESCC and healthy control serum were detected by enzyme-linked immunosorbent assay (ELISA), and the clinical parameters were analyzed. We established ESCC cells with stathmin overexpression or knockdown and then evaluated the effects of stathmin on invasion and metastasis in ESCC. Differentially expressed genes were analyzed by Human Transcriptome Array and confirmed by RT-PCR. The expression levels of the integrin family, focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) were detected by immunoblotting. RESULTS: Serum levels of stathmin were significantly higher in ESCC than in control serum and associated with lymph node metastasis, tumor stage and size. Furthermore, we found that stathmin promoted migration and invasion of ESCC cells in vitro and in vivo. In addition, we confirmed that the activation of the integrinα5ß1/FAK/ERK pathway is increased in stathmin-overexpression cells and accelerates cell motility by enhancing cell adhesion ability. CONCLUSION: Stathmin may predict a potential metastasis biomarker for ESCC.

7.
Oncotarget ; 6(21): 18445-59, 2015 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-26090615

RESUMEN

Here we demonstrated that sepantronium bromide (YM155), a survivin suppressant, inhibited esophageal squamous-cell carcinoma (ESCC) growth in mice bearing human ESCC xenografts without affecting body weight. In cell culture, YM155 decreased survivin levels and caused PARP-1 activation, poly-ADP polymer formation, and AIF translocation from the cytosol to the nucleus. Genetic knockdown of PARP-1 or AIF abrogated YM155-induced parthanatos cell death. Furthermore, FOS, JUN and c-MYC gene transcription, which is stimulated by activated PARP-1, was increased following YM155 treatment. Our data demonstrate that YM155 did not trigger apoptosis, but induced parthanatos, a cell death dependent on PARP-1 hyper-activation, and support clinical development of YM155 in ESCC.


Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Imidazoles/farmacología , Naftoquinonas/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Western Blotting , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Relación Dosis-Respuesta a Droga , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Ratones Desnudos , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , Análisis de Secuencia por Matrices de Oligonucleótidos , Poli(ADP-Ribosa) Polimerasas/genética , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Survivin , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética
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