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1.
Proc Natl Acad Sci U S A ; 120(11): e2215732120, 2023 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-36893266

RESUMEN

Immunotherapy of PD-L1/PD-1 blockage elicited impressive clinical benefits for cancer treatment. However, the relative low response and therapy resistance highlight the need to better understand the molecular regulation of PD-L1 in tumors. Here, we report that PD-L1 is a target of UFMylation. UFMylation of PD-L1 destabilizes PD-L1 by synergizing its ubiquitination. Inhibition of PD-L1 UFMylation via silencing of UFL1 or Ubiquitin-fold modifier 1 (UFM1), or the defective UFMylation of PD-L1, stabilizes the PD-L1 in multiple human and murine cancer cells, and undermines antitumor immunity in vitro and mice, respectively. Clinically, UFL1 expression was decreased in multiple cancers and lower expression of UFL1 negatively correlated with the response of anti-PD1 therapy in melanoma patients. Moreover, we identified a covalent inhibitor of UFSP2 that promoted the UFMylation activity and contributed to the combination therapy with PD-1 blockade. Our findings identified a previously unrecognized regulator of PD-L1 and highlighted UFMylation as a potential therapeutic target.


Asunto(s)
Antígeno B7-H1 , Melanoma , Humanos , Animales , Ratones , Escape del Tumor , Receptor de Muerte Celular Programada 1/genética , Ubiquitinación , Cisteína Endopeptidasas
3.
FASEB J ; 37(11): e23221, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37795761

RESUMEN

Ubiquitin fold modifier 1 is a small ubiquitin-like protein modifier that is essential for embryonic development of metazoans. Although UFMylation has been connected to endoplasmic reticulum homeostasis, the underlying mechanisms and the relevant cellular targets are largely unknown. Here, we show that HRD1, a ubiquitin ligase of ER-associated protein degradation (ERAD), is a novel substrate of UFM1 conjugation. HRD1 interacts with UFMylation components UFL1 and DDRGK1 and is UFMylated at Lys610 residue. In UFL1-depleted cells, the stability of HRD1 is increased and its ubiquitination modification is reduced. In the event of ER stress, the UFMylation and ubiquitination modification of HRD1 is gradually inhibited over time. Alteration of HRD1 Lys610 residue to arginine impairs its ability to degrade unfolded or misfolded proteins to disturb protein processing in ER. These results suggest that UFMylation of HRD1 facilitates ERAD function to maintain ER homeostasis.


Asunto(s)
Estrés del Retículo Endoplásmico , Ubiquitina-Proteína Ligasas , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Proteínas/metabolismo , Retículo Endoplásmico/metabolismo , Ubiquitina/metabolismo , Homeostasis , Degradación Asociada con el Retículo Endoplásmico
4.
EMBO Rep ; 23(4): e52984, 2022 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-35107856

RESUMEN

Telomerase plays a pivotal role in tumorigenesis by both telomere-dependent and telomere-independent activities, although the underlying mechanisms are not completely understood. Using single-sample gene set enrichment analysis (ssGSEA) across 9,264 tumour samples, we observe that expression of telomerase reverse transcriptase (TERT) is closely associated with immunosuppressive signatures. We demonstrate that TERT can activate a subclass of endogenous retroviruses (ERVs) independent of its telomerase activity to form double-stranded RNAs (dsRNAs), which are sensed by the RIG-1/MDA5-MAVS signalling pathway and trigger interferon signalling in cancer cells. Furthermore, we show that TERT-induced ERV/interferon signalling stimulates the expression of chemokines, including CXCL10, which induces the infiltration of suppressive T-cell populations with increased percentage of CD4+ and FOXP3+ cells. These data reveal an unanticipated role for telomerase as a transcriptional activator of ERVs and provide strong evidence that TERT-mediated ERV/interferon signalling contributes to immune suppression in tumours.


Asunto(s)
Retrovirus Endógenos , Neoplasias , Telomerasa , Microambiente Tumoral , ARN Polimerasas Dirigidas por ADN/metabolismo , Retrovirus Endógenos/genética , Humanos , Neoplasias/inmunología , Neoplasias/virología , Telomerasa/genética , Telomerasa/metabolismo , Telómero/metabolismo , Microambiente Tumoral/genética
5.
J Biol Chem ; 298(6): 102016, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35525273

RESUMEN

Ubiquitin-fold modifier 1 (UFM1) is a recently identified ubiquitin-like posttranslational modification with important biological functions. However, the regulatory mechanisms governing UFM1 modification of target proteins (UFMylation) and the cellular processes controlled by UFMylation remain largely unknown. It has been previously shown that a UFM1-specific protease (UFSP2) mediates the maturation of the UFM1 precursor and drives the de-UFMylation reaction. Furthermore, it has long been thought that UFSP1, an ortholog of UFSP2, is inactive in many organisms, including human, because it lacks an apparent protease domain when translated from the canonical start codon (445AUG). Here, we demonstrate using the combination of site-directed mutagenesis, CRISPR/Cas9-mediated genome editing, and mass spectrometry approaches that translation of human UFSP1 initiates from an upstream near-cognate codon, 217CUG, via eukaryotic translation initiation factor eIF2A-mediated translational initiation rather than from the annotated 445AUG, revealing the presence of a catalytic protease domain containing a Cys active site. Moreover, we show that both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation of target proteins. This study demonstrates that human UFSP1 functions as an active UFM1-specific protease, thus contributing to our understanding of the UFMylation/de-UFMylation process.


Asunto(s)
Cisteína Endopeptidasas , Péptido Hidrolasas , Proteínas , Codón Iniciador/genética , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismo , Endopeptidasas/metabolismo , Humanos , Péptido Hidrolasas/metabolismo , Biosíntesis de Proteínas , Procesamiento Proteico-Postraduccional , Proteínas/metabolismo , Ubiquitina/metabolismo
6.
Nature ; 550(7674): 133-136, 2017 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-28953887

RESUMEN

Targeted BRAF inhibition (BRAFi) and combined BRAF and MEK inhibition (BRAFi and MEKi) therapies have markedly improved the clinical outcomes of patients with metastatic melanoma. Unfortunately, the efficacy of these treatments is often countered by the acquisition of drug resistance. Here we investigated the molecular mechanisms that underlie acquired resistance to BRAFi and to the combined therapy. Consistent with previous studies, we show that resistance to BRAFi is mediated by ERK pathway reactivation. Resistance to the combined therapy, however, is mediated by mechanisms independent of reactivation of ERK in many resistant cell lines and clinical samples. p21-activated kinases (PAKs) become activated in cells with acquired drug resistance and have a pivotal role in mediating resistance. Our screening, using a reverse-phase protein array, revealed distinct mechanisms by which PAKs mediate resistance to BRAFi and the combined therapy. In BRAFi-resistant cells, PAKs phosphorylate CRAF and MEK to reactivate ERK. In cells that are resistant to the combined therapy, PAKs regulate JNK and ß-catenin phosphorylation and mTOR pathway activation, and inhibit apoptosis, thereby bypassing ERK. Together, our results provide insights into the molecular mechanisms underlying acquired drug resistance to current targeted therapies, and may help to direct novel drug development efforts to overcome acquired drug resistance.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Melanoma/tratamiento farmacológico , Melanoma/genética , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Transducción de Señal/efectos de los fármacos , Quinasas p21 Activadas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/química , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melanoma/enzimología , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/química , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-raf/química , Proteínas Proto-Oncogénicas c-raf/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , beta Catenina/química , beta Catenina/metabolismo , Quinasas p21 Activadas/antagonistas & inhibidores , Quinasas p21 Activadas/genética
7.
Int J Mol Sci ; 23(17)2022 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-36077510

RESUMEN

Endogenous retroviruses (ERVs), deriving from exogenous retroviral infections of germ line cells occurred millions of years ago, represent ~8% of human genome. Most ERVs are highly inactivated because of the accumulation of mutations, insertions, deletions, and/or truncations. However, it is becoming increasingly apparent that ERVs influence host biology through genetic and epigenetic mechanisms under particular physiological and pathological conditions, which provide both beneficial and deleterious effects for the host. For instance, certain ERVs expression is essential for human embryonic development. Whereas abnormal activation of ERVs was found to be involved in numbers of human diseases, such as cancer and neurodegenerative diseases. Therefore, understanding the mechanisms of regulation of ERVs would provide insights into the role of ERVs in health and diseases. Here, we provide an overview of mechanisms of transcriptional regulation of ERVs and their dysregulation in human diseases.


Asunto(s)
Retrovirus Endógenos , Infecciones por Retroviridae , Retrovirus Endógenos/genética , Epigénesis Genética , Genoma Humano , Humanos , Infecciones por Retroviridae/genética
8.
FASEB J ; 34(3): 4178-4188, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31950551

RESUMEN

Telomerase plays a pivotal role in tumorigenesis by maintaining telomere homeostasis, a hallmark of cancer. However, the mechanisms by which telomerase is reactivated or upregulated during tumorigenesis remain incompletely understood. Here, we report that the Hippo pathway effector Yes-associated protein (YAP) regulates the expression of human telomerase reverse transcriptase (hTERT). Ectopic expression or physiological activation of YAP increases hTERT expression, whereas knockdown of YAP decreases the expression of hTERT. YAP binds to the hTERT promoter through interaction with the TEA domain family transcription factors and activates hTERT transcription. Furthermore, sustained YAP hyperactivation promotes telomerase activity and extends telomere length, with increased hTERT expression. In addition, we show that hTERT expression is positively correlated with YAP activation in human liver cancer tissues. Together, our results demonstrate that YAP promotes hTERT expression, which could contribute to tumor progression.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Telomerasa/metabolismo , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Línea Celular , Inmunoprecipitación de Cromatina , Regulación Enzimológica de la Expresión Génica/genética , Regulación Enzimológica de la Expresión Génica/fisiología , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Células HeLa , Vía de Señalización Hippo , Humanos , Células MCF-7 , Microscopía Fluorescente , Regiones Promotoras Genéticas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Telomerasa/genética , Factores de Transcripción/genética , Proteínas Señalizadoras YAP
9.
Nucleic Acids Res ; 47(8): 4124-4135, 2019 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-30783677

RESUMEN

A proper DNA damage response (DDR) is essential to maintain genome integrity and prevent tumorigenesis. DNA double-strand breaks (DSBs) are the most toxic DNA lesion and their repair is orchestrated by the ATM kinase. ATM is activated via the MRE11-RAD50-NBS1 (MRN) complex along with its autophosphorylation at S1981 and acetylation at K3106. Activated ATM rapidly phosphorylates a vast number of substrates in local chromatin, providing a scaffold for the assembly of higher-order complexes that can repair damaged DNA. While reversible ubiquitination has an important role in the DSB response, modification of the newly identified ubiquitin-like protein ubiquitin-fold modifier 1 and the function of UFMylation in the DDR is largely unknown. Here, we found that MRE11 is UFMylated on K282 and this UFMylation is required for the MRN complex formation under unperturbed conditions and DSB-induced optimal ATM activation, homologous recombination-mediated repair and genome integrity. A pathogenic mutation MRE11(G285C) identified in uterine endometrioid carcinoma exhibited a similar cellular phenotype as the UFMylation-defective mutant MRE11(K282R). Taken together, MRE11 UFMylation promotes ATM activation, DSB repair and genome stability, and potentially serves as a therapeutic target.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica , Proteína Homóloga de MRE11/genética , Procesamiento Proteico-Postraduccional , Proteínas/genética , Reparación del ADN por Recombinación , Células A549 , Acetilación , Ácido Anhídrido Hidrolasas , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Cromatina/metabolismo , Cromatina/patología , Roturas del ADN de Doble Cadena , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , ADN de Neoplasias/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Humanos , Proteína Homóloga de MRE11/antagonistas & inhibidores , Proteína Homóloga de MRE11/metabolismo , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Osteoblastos/metabolismo , Osteoblastos/patología , Fosforilación , Unión Proteica , Proteínas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ubiquitinación
10.
Phytother Res ; 35(10): 5767-5780, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34374127

RESUMEN

Studies have found that salidroside, isolated from Rhodiola rosea L, has various pharmacological activities, but there have been no studies on the effects of salidroside on brain hippocampal senescence. The purpose of this study was to investigate the mechanistic role of salidroside in hippocampal neuron senescence and injury. In this study, long-term cultured primary rat hippocampal neurons and naturally aged C57 mice were treated with salidroside. The results showed that salidroside increased the viability and MAP2 expression, reduced ß-galactosidase (ß-gal) levels of rat primary hippocampal neurons. Salidroside also improved cognition dysfunction in ageing mice and alleviated neuronal degeneration in the ageing mice CA1 region. Moreover, salidroside decreased the levels of oxidative stress and p21, p16 protein expressions of hippocampal neurons and ageing mice. Salidroside promoted telomerase reverse transcriptase (TERT) protein expression via the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway. In conclusion, our findings suggest that salidroside has the potential to be used as a therapeutic strategy for anti-ageing and ageing-related disease treatment.


Asunto(s)
Fármacos Neuroprotectores , Proteínas Proto-Oncogénicas c-akt , Envejecimiento , Animales , Glucósidos , Hipocampo/metabolismo , Ratones , Neuronas , Fármacos Neuroprotectores/farmacología , Fenoles , Fosfatidilinositol 3-Quinasa , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas
11.
EMBO Rep ; 19(10)2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30126922

RESUMEN

Progressive attrition of telomeres triggers DNA damage response (DDR) and limits the regenerative capacity of adult stem cells during mammalian aging. Intriguingly, telomere integrity is not only determined by telomere length but also by the epigenetic status of telomeric/sub-telomeric regions. However, the functional interplay between DDR induced by telomere shortening and epigenetic modifications in aging remains unclear. Here, we show that deletion of Gadd45a improves the maintenance and function of intestinal stem cells (ISCs) and prolongs lifespan of telomerase-deficient mice (G3Terc-/-). Mechanistically, Gadd45a facilitates the generation of a permissive chromatin state for DDR signaling by inducing base excision repair-dependent demethylation of CpG islands specifically at sub-telomeric regions of short telomeres. Deletion of Gadd45a promotes chromatin compaction in sub-telomeric regions and attenuates DDR initiation at short telomeres of G3Terc-/- ISCs. Treatment with a small molecule inhibitor of base excision repair reduces DDR and improves the maintenance and function of G3Terc-/- ISCs. Taken together, our study proposes a therapeutic approach to enhance stem cell function and prolong lifespan by targeting epigenetic modifiers.


Asunto(s)
Proteínas de Ciclo Celular/genética , Epigénesis Genética/genética , Proteínas Nucleares/genética , ARN/genética , Telomerasa/genética , Telómero/genética , Envejecimiento/genética , Envejecimiento/metabolismo , Animales , Islas de CpG/genética , Daño del ADN/genética , Mucosa Intestinal/metabolismo , Ratones , Ratones Noqueados , Células Madre/metabolismo
12.
Clin Exp Pharmacol Physiol ; 47(3): 357-364, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31799699

RESUMEN

Telomeres are specialized genomic structures that protect chromosomal ends to maintain genomic stability. Telomeric length is primarily regulated by the telomerase complex, essentially consisting of an RNA template (TERC), an enzymatic subunit (telomerase reverse transcriptase, TERT). In humans, telomerase activity is repressed during embryonic differentiation and is absent in most somatic cells. However, it is upregulated or reactivated in 80%-90% of the primary tumours in humans. The human TERT (hTERT) plays a pivotal role in cellular immortality and tumourigenesis. However, the molecular mechanisms of telomerase functioning in cancer have not been fully understood beyond the telomere maintenance. Several research groups, including ours, have demonstrated that hTERT possesses vital functions independent of its telomere maintenance, including angiogenesis, inflammation, cancer cell stemness, and epithelial-mesenchymal transformation (EMT). All these telomere-independent activities of hTERT may contribute to the regulation of the dynamics and homeostasis of the tumour microenvironment (TME), thereby promoting tumour growth and development. Cancer progression and metastasis largely depend upon the interactions between cancer cells and their microenvironment. In this review, the involvement of TERT in the tumour microenvironment and the underlying implications in cancer therapeutics have been summarized.


Asunto(s)
Neoplasias/metabolismo , Células Madre Neoplásicas/metabolismo , Telomerasa/metabolismo , Microambiente Tumoral/fisiología , Animales , Carcinogénesis/metabolismo , Carcinogénesis/patología , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Humanos , Invasividad Neoplásica/patología , Neoplasias/patología , Células Madre Neoplásicas/patología , Telomerasa/fisiología
13.
Clin Exp Pharmacol Physiol ; 45(7): 704-710, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29381831

RESUMEN

Polymerase I and transcript release factor (Ptrf, also known as Cavin1) is an essential component in the biogenesis and function of caveolae. Ptrf knockout mice or patients with PTRF mutations exhibit numerous pathologies including markedly aberrant fuel metabolism, lipodystrophy and muscular dystrophy. In this study, we generated Ptrf transgenic mice to explore its function in vivo. Compared with wild-type (WT) mice, we found that the Ptrf transgenic mice showed obesity with an increased level of ALT (alanine aminotransferase) and AST (aspartate transaminase). Ptrf transgenic mice exhibited severe fat degeneration and a higher degree of fat accumulation in the liver compared with WT mice. Consistently, we found that the expression of the fat synthesis gene, Fasn, was increased in the liver of Ptrf transgenic mice. Thus, Ptrf transgenic mice would be a good model for investigating the molecular mechanism and therapeutic targets of obesity and fatty liver associated diseases.


Asunto(s)
Hígado Graso/genética , Proteínas de la Membrana/genética , Obesidad/genética , Proteínas de Unión al ARN/genética , Alanina Transaminasa/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Hígado Graso/enzimología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Obesidad/enzimología , Proteínas de Unión al ARN/metabolismo
14.
Nucleic Acids Res ; 44(18): 8693-8703, 2016 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-27325744

RESUMEN

Angiogenesis is recognized as an important hallmark of cancer. Although telomerase is thought to be involved in tumor angiogenesis, the evidence and underlying mechanism remain elusive. Here, we demonstrate that human telomerase reverse transcriptase (hTERT) activates vascular epithelial growth factor (VEGF) gene expression through interactions with the VEGF promoter and the transcription factor Sp1. hTERT binds to Sp1 in vitro and in vivo and stimulates angiogenesis in a manner dependent on Sp1. Deletion of the mTert gene in the first generation of Tert null mice compromised tumor growth, with reduced VEGF expression. In addition, we show that hTERT expression levels are positively correlated with those of VEGF in human gastric tumor samples. Together, our results demonstrate that hTERT facilitates tumor angiogenesis by up-regulating VEGF expression through direct interactions with the VEGF gene and the Sp1 transcription factor. These results provide novel insights into hTERT function in tumor progression in addition to its role in telomere maintenance.


Asunto(s)
Neovascularización Patológica/metabolismo , Factor de Transcripción Sp1/metabolismo , Telomerasa/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Carcinogénesis/metabolismo , Carcinogénesis/patología , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Células HeLa , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ratones Endogámicos C57BL , Neovascularización Fisiológica , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Regiones Promotoras Genéticas , Unión Proteica/genética , Neoplasias Gástricas/irrigación sanguínea , Neoplasias Gástricas/genética , Transcripción Genética , Regulación hacia Arriba/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
15.
Blood ; 126(5): 620-8, 2015 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-26012568

RESUMEN

Wild-type p53-induced phosphatase 1 (Wip1), a phosphatase previously considered as an oncogene, has been implicated in the regulation of thymus homeostasis and neutrophil maturation. However, the role of Wip1 in B-cell development is unknown. We show that Wip1-deficient mice exhibit a significant reduction of B-cell numbers in the bone marrow, peripheral blood, and spleen. A reciprocal transplantation approach revealed a cell-intrinsic defect in early B-cell precursors caused by Wip1 deficiency. Further experiments revealed that Wip1 deficiency led to a sustained activation of p53 in B cells, which led to increased level of apoptosis in the pre-B-cell compartment. Notably, the impairment of B-cell development in Wip1-deficient mice was completely rescued by genetic ablation of p53, but not p21. Therefore, loss of Wip1 phosphatase induces a p53-dependent, but p21-independent, mechanism that impairs B-cell development by enhancing apoptosis in early B-cell precursors. Moreover, Wip1 deficiency exacerbated a decline in B-cell development caused by aging as evidenced in mice with aging and mouse models with serial competitive bone marrow transplantation, respectively. Our present data indicate that Wip1 plays a critical role in maintaining antigen-independent B-cell development in the bone marrow and preventing an aging-related decline in B-cell development.


Asunto(s)
Linfocitos B/citología , Linfocitos B/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Envejecimiento/inmunología , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Apoptosis , Linfocitos B/inmunología , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Diferenciación Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Femenino , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfoproteínas Fosfatasas/deficiencia , Fosfoproteínas Fosfatasas/genética , Células Precursoras de Linfocitos B/citología , Células Precursoras de Linfocitos B/inmunología , Células Precursoras de Linfocitos B/metabolismo , Proteína Fosfatasa 2C , Transducción de Señal
16.
J Biol Chem ; 290(52): 30813-29, 2015 Dec 25.
Artículo en Inglés | MEDLINE | ID: mdl-26518879

RESUMEN

Mutations of human telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) are associated with a subset of lung aging diseases, but the mechanisms by which TERC and TERT participate in lung diseases remain unclear. In this report, we show that knock-out (KO) of the mouse gene Terc or Tert causes pulmonary alveolar stem cell replicative senescence, epithelial impairment, formation of alveolar sacs, and characteristic inflammatory phenotype. Deficiency in TERC or TERT causes a remarkable elevation in various proinflammatory cytokines, including IL-1, IL-6, CXCL15 (human IL-8 homolog), IL-10, TNF-α, and monocyte chemotactic protein 1 (chemokine ligand 2 (CCL2)); decrease in TGF-ß1 and TGFßRI receptor in the lungs; and spillover of IL-6 and CXCL15 into the bronchoalveolar lavage fluids. In addition to increased gene expressions of α-smooth muscle actin and collagen 1α1, suggesting myofibroblast differentiation, TERC deficiency also leads to marked cellular infiltrations of a mononuclear cell population positive for the leukocyte common antigen CD45, low-affinity Fc receptor CD16/CD32, and pattern recognition receptor CD11b in the lungs. Our data demonstrate for the first time that telomerase deficiency triggers alveolar stem cell replicative senescence-associated low-grade inflammation, thereby driving pulmonary premature aging, alveolar sac formation, and fibrotic lesion.


Asunto(s)
Enfermedades Pulmonares/inmunología , Alveolos Pulmonares/enzimología , Células Madre/citología , Telomerasa/deficiencia , Animales , Senescencia Celular , Femenino , Humanos , Interleucina-1/genética , Interleucina-1/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Pulmón/citología , Pulmón/inmunología , Enfermedades Pulmonares/enzimología , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Alveolos Pulmonares/citología , Alveolos Pulmonares/inmunología , ARN/genética , Células Madre/inmunología , Telomerasa/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
17.
Am J Physiol Cell Physiol ; 308(5): C385-96, 2015 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-25500738

RESUMEN

Lipid metabolic disturbances are related to many diseases, such as obesity, diabetes, and certain cancers. Notably, lipid metabolic disturbances have been reported to be a risk factor for colorectal cancer. Nuclear receptors act as ligand-dependent transcription regulators and play key roles in the regulation of body lipid metabolism and the development of many cancers. Retinoic acid receptor-related orphan receptor α (RORα) is a nuclear receptor and can regulate several lipid metabolism genes in certain cancers. Herein, we demonstrate that the conditioned medium from adipocytes has a proproliferative and promigratory effect on colorectal cancer cells and enhances angiogenesis in chicken embryonic chorioallantoic membranes. In addition, the conditioned medium leads to a decrease in the expression of RORα and its target genes. Meanwhile, RORα and its target gene expressions are lower in human colorectal tumor tissue compared with control colorectal tissue. Activation of RORα inhibits the effect of conditioned medium on the proliferation and migration of colorectal cancer cells as well as the angiogenesis in chicken embryonic allantoic membranes. In colorectal cancer cells, the putative ligand of RORα, cholesterol sulfate (CS), prevents cell cycle progression at the G1/S boundary and concurrently modulates the expression of cell cycle-regulatory genes in colorectal cancer cell. CS inhibits angiogenesis in chicken embryonic chorioallantoic membranes and concurrently decreases the mRNA expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α as well as the secretion of VEGF. In addition, lipogenic gene expression is higher in human colorectal tumor tissue compared with control colorectal tissue. CS inhibits the expression of lipogenic genes in colorectal cancer cells. These results suggest that RORα could represent a direct link between local lipid metabolism of colorectal tissue and colorectal cancer. Therefore, the reduction of the expression of RORα could represent a potential warning sign of colorectal cancer.


Asunto(s)
Movimiento Celular/fisiología , Proliferación Celular/fisiología , Membrana Corioalantoides/fisiología , Neoplasias Colorrectales/metabolismo , Medios de Cultivo Condicionados/farmacología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/biosíntesis , Células 3T3 , Adipocitos/fisiología , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Membrana Corioalantoides/efectos de los fármacos , Neoplasias Colorrectales/patología , Humanos , Ratones , Neovascularización Fisiológica/efectos de los fármacos , Neovascularización Fisiológica/fisiología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores
18.
FASEB J ; 27(11): 4375-83, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23884427

RESUMEN

Telomerase plays a pivotal role in the pathology of aging and cancer by controlling telomere length and integrity. However, accumulating evidence indicates that telomerase reverse transcriptase may have fundamental biological functions independent of its enzymatic activity in telomere maintenance. In this study, the ectopic expression of human telomerase reverse transcriptase (hTERT) and its catalytic mutant hTERT K626A induced cancer cell invasion accompanied by the up-regulation of the metalloproteinases (MMPs) MMP1, -3, -9, and -10. Both hTERT and hTERT K626A induced MMP9 mRNA expression and promoter activity in an NF-κB-dependent manner. hTERT and hTERT K626A also regulated the expression of several NF-κB target genes in cancer cell lines. Furthermore, both hTERT and hTERT K626A interacted with NF-κB p65 and increased NF-κB p65 nuclear accumulation and DNA binding. A mammalian 1-hybrid assay showed a functional interplay between hTERT and NF-κB p65 that may mediate NF-κB-dependent transcription activation in cells. Together, these data reveal a telomere-independent role for telomerase as a transcriptional modulator of the NF-κB signaling pathway and a possible contributor to cancer development and progression.


Asunto(s)
Metaloproteinasas de la Matriz/metabolismo , Telomerasa/metabolismo , Factor de Transcripción ReIA/metabolismo , Transcripción Genética , Transporte Activo de Núcleo Celular , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Metaloproteinasas de la Matriz/genética , Mutación , Regiones Promotoras Genéticas , Unión Proteica , Telomerasa/genética , Regulación hacia Arriba
19.
Clin Exp Pharmacol Physiol ; 41(3): 169-73, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24471649

RESUMEN

1. Previously, we showed that the essential caveolar component polymerase I and transcript release factor (PTRF) was upregulated and promoted caveolae formation in senescent cells. In addition, we found that overexpression of PTRF increased the number of caveolae and induced cellular senescence. 2. Unresponsiveness to growth factor is one of the fundamental characteristics of senescent cells, although normal levels of receptors and downstream signalling molecules are present in senescent cells. 3. Herein, we investigated the role of PTRF in the regulation of platelet-derived growth factor (PDGF) signalling in young and senescent cells. 4. We first confirmed that PTRF was upregulated in senescent human fibroblasts and aged mouse tissues. We then examined the activation of extracellular signal-regulated kinases (ERK) in young and senescent cells after PDGF stimulation. 5. Our results show that expression of PDGF receptors (PDGFRs) was not altered during cellular senescence. Interestingly, phosphorylation of ERK1/2 was induced upon PDGF stimulation of young, replicating cells but not senescent cells. Induction of ERK1/2 phosphorylation was impaired in senescent cells and PTRF-overexpressing presenescent cells. Furthermore, our results show that PTRF interacts with PDGFRs and this interaction is increased in senescent cells. 6. These results suggest that the unresponsiveness of senescent fibroblasts to PDGF stimulation may be due to increased levels of PTRF and the formation of caveolae, which, in turn sequester growth receptors, such as PDGFR and its signalling molecules.


Asunto(s)
Senescencia Celular/genética , Proteínas de Unión al ARN/genética , Receptores del Factor de Crecimiento Derivado de Plaquetas/genética , Transducción de Señal/genética , Animales , Línea Celular , Fibroblastos , Humanos , Sistema de Señalización de MAP Quinasas/genética , Ratones , Fosforilación/genética , Proteínas de Unión al ARN/metabolismo , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Regulación hacia Arriba/genética
20.
Biophys Rep ; 10(4): 230-240, 2024 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-39281196

RESUMEN

Met1-linked ubiquitination (Met1-Ub), also known as linear ubiquitination, is a newly identified atypical type of polyubiquitination that is assembled via the N-terminal methionine (Met1) rather than an internal lysine (Lys) residue of ubiquitin. The linear ubiquitin chain assembly complex (LUBAC) composed of HOIP, HOIL-1L and SHARPIN is the sole E3 ubiquitin ligase that specifically generates Met1-linked ubiquitin chains. The physiological role of LUBAC-mediated Met1-Ub has been first described as activating NF-κB signaling through the Met1-Ub modification of NEMO. However, accumulating evidence shows that Met1-Ub is broadly involved in other cellular pathways including MAPK, Wnt/ß-Catenin, PI3K/AKT and interferon signaling, and participates in various cellular processes including angiogenesis, protein quality control and autophagy, suggesting that Met1-Ub harbors a potent signaling capacity. Here, we review the formation and cellular functions of Met1-linked ubiquitin chains, with an emphasis on the recent advances in the cellular mechanisms by which Met1-Ub controls signaling transduction.

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