RESUMEN

Ferroptosis has attracted extensive interest from cancer researchers due to its substantial potential as a therapeutic target. The role of LATS2, a core component of the Hippo pathway cascade, in ferroptosis initiation in hepatoblastoma (HB) has not yet been investigated. Furthermore, the underlying mechanism of decreased LATS2 expression remains largely unknown. In the present study, we demonstrated decreased LATS2 expression in HB and that LATS2 overexpression inhibits HB cell proliferation by inducing ferroptosis. Increased LATS2 expression reduced glycine and cysteine concentrations via the ATF4/PSAT1 axis. Physical binding between YAP1/ATF4 and the PSAT1 promoter was confirmed through ChIP‒qPCR. Moreover, METTL3 was identified as the writer of the LATS2 mRNA m6A modification at a specific site in the 5' UTR. Subsequently, YTHDF2 recognizes the m6A modification site and recruits the CCR4-NOT complex, leading to its degradation by mRNA deadenylation. In summary, N6-methyladenosine modification of LATS2 facilitates its degradation. Reduced LATS2 expression promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis. Targeting LATS2 is a potential strategy for HB therapy.

Asunto(s)

Factor de Transcripción Activador 4 , Adenosina , Ferroptosis , Hepatoblastoma , Proteínas Serina-Treonina Quinasas , Proteínas Supresoras de Tumor , Proteínas Señalizadoras YAP , Humanos , Hepatoblastoma/metabolismo , Hepatoblastoma/genética , Hepatoblastoma/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Señalizadoras YAP/metabolismo , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Ferroptosis/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Línea Celular Tumoral , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Animales , Proliferación Celular , Ratones Desnudos , Ratones , Regulación Neoplásica de la Expresión Génica , Metiltransferasas

RESUMEN

Background: Cancer-associated fibroblasts (CAFs) are the key components of the immune barrier in liver cancer. Therefore, gaining a deeper understanding of the heterogeneity and intercellular communication of CAFs holds utmost importance in boosting immunotherapy effectiveness and improving clinical outcomes. Methods: A comprehensive analysis by combing single-cell, bulk, and spatial transcriptome profiling with multiplexed immunofluorescence was conducted to unravel the complexities of CAFs in liver cancer. Results: Through an integrated approach involving 235 liver cancer scRNA-seq samples encompassing over 1.2 million cells, we found that CAFs were particularly increased in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). FAP + fibroblasts were identified as the dominant subtype of CAFs, and which were mainly involved in extracellular matrix organization and angiogenesis. These CAFs were enriched in the tumor boundary of HCC, but diffusely scattered within ICC. The DAB2 + and SPP1 + tumor-associated macrophages (TAMs) reinforce the function of FAP + CAFs through signals such as TGF-ß, PDGF, and ADM. Notably, the interaction between DAB2 + TAMs and FAP + CAFs promoted the formation of immune barrier and correlated with poorer patient survival, non-response to immunotherapy in HCC. High FAP and DAB2 immunohistochemical scores predicted shorter survival and higher serum AFP concentration in a local clinical cohort of 90 HCC patients. Furthermore, this communication pattern might be applicable to other solid malignancies as well. Conclusions: The interaction between DAB2 + TAMs and FAP + CAFs appears crucial in shaping the immune barrier. Strategies aimed at disrupting this communication or inhibiting the functions of FAP + CAFs could potentially enhance immunotherapy effectiveness and improve clinical outcomes.

Asunto(s)

Fibroblastos Asociados al Cáncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Microambiente Tumoral , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/inmunología , Fibroblastos Asociados al Cáncer/metabolismo , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/inmunología , Microambiente Tumoral/inmunología , Macrófagos/metabolismo , Macrófagos/inmunología , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Colangiocarcinoma/terapia , Colangiocarcinoma/patología , Colangiocarcinoma/inmunología , Colangiocarcinoma/metabolismo , Inmunoterapia/métodos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Masculino , Femenino , Endopeptidasas

RESUMEN

Cisplatin-induced renal tubular injury largely restricts the wide-spread usage of cisplatin in the treatment of malignancies. Identifying the key signaling pathways that regulate cisplatin-induced renal tubular injury is thus clinically important. PARVB, a focal adhesion protein, plays a crucial role in tumorigenesis. However, the function of PARVB in kidney disease is largely unknown. To investigate whether and how PARVB contributes to cisplatin-induced renal tubular injury, a mouse model (PARVB cKO) was generated in which PARVB gene was specifically deleted from proximal tubular epithelial cells using the Cre-LoxP system. In this study, we found depletion of PARVB in proximal tubular epithelial cells significantly attenuates cisplatin-induced renal tubular injury, including tubular cell death and inflammation. Mechanistically, PARVB associates with transforming growth factor-ß-activated kinase 1 (TAK1), a central regulator of cell survival and inflammation that is critically involved in mediating cisplatin-induced renal tubular injury. Depletion of PARVB promotes cisplatin-induced TAK1 degradation, inhibits TAK1 downstream signaling, and ultimately alleviates cisplatin-induced tubular cell damage. Restoration of PARVB or TAK1 in PARVB-deficient cells aggravates cisplatin-induced tubular cell injury. Finally, we demonstrated that PARVB regulates TAK1 protein expression through an E3 ligase ITCH-dependent pathway. PARVB prevents ITCH association with TAK1 to block its ubiquitination. Our study reveals that PARVB deficiency protects against cisplatin-induced tubular injury through regulation of TAK1 signaling and indicates targeting this pathway may provide a novel therapeutic strategy to alleviate cisplatin-induced kidney damage.

Asunto(s)

Cisplatino , Quinasas Quinasa Quinasa PAM , Ratones Noqueados , Transducción de Señal , Cisplatino/efectos adversos , Cisplatino/toxicidad , Animales , Quinasas Quinasa Quinasa PAM/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Transducción de Señal/efectos de los fármacos , Ratones , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Túbulos Renales Proximales/efectos de los fármacos , Humanos , Ratones Endogámicos C57BL , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Antineoplásicos/farmacología , Antineoplásicos/efectos adversos , Túbulos Renales/patología , Túbulos Renales/metabolismo , Túbulos Renales/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales

RESUMEN

BACKGROUND: Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness. METHODS: Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression. RESULTS: We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment. CONCLUSIONS: Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.

Asunto(s)

Neoplasias Hematológicas , Humanos , Animales , Línea Celular Tumoral , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/metabolismo , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteolisis/efectos de los fármacos , Ubiquitina-Proteína Ligasas/metabolismo , Factor de Transcripción Ikaros/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales

RESUMEN

BACKGROUND: Hepatic fibrosis, a prevalent chronic liver condition, involves excessive extracellular matrix production associated with aberrant wound healing. Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis, activated by inflammatory factors such as sphingosine 1-phosphate (S1P). Despite S1P's involvement in fibrosis, its specific role and downstream pathway in HSCs remain controversial. METHODS: In this study, we investigated the regulatory role of S1P/S1P receptor (S1PR) in Hippo-YAP activation in both LX-2 cell lines and primary HSCs. Real-time PCR, western blot, pharmacological inhibitors, siRNAs, and Rho activity assays were adopted to address the molecular mechanisms of S1P mediated YAP activation. RESULTS: Serum and exogenous S1P significantly increased the expression of YAP target genes in HSCs. Pharmacologic inhibitors and siRNA-mediated knockdowns of S1P receptors showed S1P receptor 2 (S1PR2) as the primary mediator for S1P-induced CTGF expression in HSCs. Results using siRNA-mediated knockdown, Verteporfin, and Phospho-Tag immunoblots showed that S1P-S1PR2 signaling effectively suppressed the Hippo kinases cascade, thereby activating YAP. Furthermore, S1P increased RhoA activities in cells and ROCK inhibitors effectively blocked CTGF induction. Cytoskeletal-perturbing reagents were shown to greatly modulate CTGF induction, suggesting the important role of actin cytoskeleton in S1P-induced YAP activation. Exogeneous S1P treatment was enough to increase the expression of COL1A1 and α-SMA, that were blocked by YAP specific inhibitor. CONCLUSIONS: Our data demonstrate that S1P/S1PR2-Src-RhoA-ROCK axis leads to Hippo-YAP activation, resulting in the up-regulation of CTGF, COL1A1 and α-SMA expression in HSCs. Therefore, S1PR2 may represent a potential therapeutic target for hepatic fibrosis.

Asunto(s)

Factor de Crecimiento del Tejido Conjuntivo , Células Estrelladas Hepáticas , Lisofosfolípidos , Transducción de Señal , Esfingosina , Factores de Transcripción , Proteínas Señalizadoras YAP , Quinasas Asociadas a rho , Proteína de Unión al GTP rhoA , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/genética , Lisofosfolípidos/metabolismo , Lisofosfolípidos/farmacología , Humanos , Quinasas Asociadas a rho/metabolismo , Quinasas Asociadas a rho/genética , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Proteínas Señalizadoras YAP/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/genética , Línea Celular , Cirrosis Hepática/metabolismo , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Familia-src Quinasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Receptores de Lisoesfingolípidos/metabolismo , Receptores de Lisoesfingolípidos/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Vía de Señalización Hippo

RESUMEN

Lineage plasticity in small cell lung carcinoma (SCLC) causes therapeutic difficulties. This study aimed to investigate the pathological findings of plasticity in SCLC, focusing on combined SCLC, and elucidate the involvement of YAP1 and other transcription factors. We analysed 100 surgically resected SCLCs through detailed morphological observations and immunohistochemistry for YAP1 and other transcription factors. Component-by-component next-generation sequencing (n = 15 pairs) and immunohistochemistry (n = 35 pairs) were performed on the combined SCLCs. Compared with pure SCLCs (n = 65), combined SCLCs (n = 35) showed a significantly larger size, higher expression of NEUROD1, and higher frequency of double-positive transcription factors (p = 0.0009, 0.04, and 0.019, respectively). Notably, 34% of the combined SCLCs showed morphological mosaic patterns with unclear boundaries between the SCLC and its partner. Combined SCLCs not only had unique histotypes as partners but also represented different lineage plasticity within the partner. NEUROD1-dominant combined SCLCs had a significantly higher proportion of adenocarcinomas as partners, whereas POU2F3-dominant combined SCLCs had a significantly higher proportion of squamous cell carcinomas as partners (p = 0.006 and p = 0.0006, respectively). YAP1 expression in SCLC components was found in 80% of combined SCLCs and 62% of pure SCLCs, often showing mosaic-like expression. Among the combined SCLCs with component-specific analysis, the identical TP53 mutation was found in 10 pairs, and the identical Rb1 abnormality was found in 2 pairs. On immunohistochemistry, the same abnormal p53 pattern was found in 34 pairs, and Rb1 loss was found in 24 pairs. In conclusion, combined SCLC shows a variety of pathological plasticity. Although combined SCLC is more plastic than pure SCLC, pure SCLC is also a phenotypically plastic tumour. The morphological mosaic pattern and YAP1 mosaic-like expression may represent ongoing lineage plasticity. This study also identified the relationship between transcription factors and partners in combined SCLC. Transcription factors may be involved in differentiating specific cell lineages beyond just 'neuroendocrine'.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Factores de Transcripción , Proteínas Señalizadoras YAP , Humanos , Proteínas Señalizadoras YAP/metabolismo , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Masculino , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Femenino , Persona de Mediana Edad , Anciano , Inmunohistoquímica , Linaje de la Célula , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Mutación , Plasticidad de la Célula , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration. Dysregulation of long non-coding RNAs (lncRNAs) has been implicated in ALS pathogenesis but their roles remain unclear. Previous studies found lnc-ABCA12-3 was downregulated in ALS patients. We aim to characterize the expression and function of lnc-ABCA12-3 in ALS and explore its mechanisms of action. Lnc-ABCA12-3 expression was analyzed in PBMCs from ALS patients and correlated with clinical outcomes. Effect of modulating lnc-ABCA12-3 expression was assessed in cell models using assays of apoptosis, protein homeostasis and pathway analysis. RNA pull-down and interaction studies were performed to identify lnc-ABCA12-3 binding partners. Lnc-ABCA12-3 was downregulated in ALS patients, correlating with faster progression and shorter survival. Overexpression of lnc-ABAC12-3 conferred protection against oxidative stress-induced apoptosis, while knockdown lnc-ABCA12-3 enhanced cell death. Lnc-ABCA12-3 maintained protein quality control pathways, including ubiquitination, autophagy and stress granule formation, by regulating the ubiquitin shuttle protein UBQLN1. This study identified lnc-ABCA12-3 as a novel regulatory lncRNA implicated in ALS pathogenesis by modulating cellular survival and stress responses through interactions with UBQLN1, influencing disease progression. Lnc-ABCA12-3 may influence ALS through regulating protein homeostasis pathways.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales , Esclerosis Amiotrófica Lateral , Apoptosis , Proteínas Relacionadas con la Autofagia , Regulación hacia Abajo , ARN Largo no Codificante , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Apoptosis/genética , Femenino , Proteostasis , Masculino , Persona de Mediana Edad , Autofagia/genética , Estrés Oxidativo , Regulación de la Expresión Génica

RESUMEN

Secretogranin III (Scg3) is a diabetic retinopathy (DR)-restricted angiogenic factor identified in preclinical studies as a target for DR therapy. Previously, our group generated and characterized ML49.3, an anti-Scg3 monoclonal antibody (mAb) which we then converted into an EBP2 humanized antibody Fab fragment (hFab) with potential for clinical application. We also generated anti-Scg3 mT4 mAb and related EBP3 hFab. In this study, to identify the preferred hFab for DR therapy, we compared all four antibodies for binding, neutralizing and therapeutic activities in vitro and in vivo. Octet binding kinetics analyses revealed that ML49.3 mAb, EBP2 hFab, mT4 mAb and EBP3 hFab have Scg3-binding affinities of 35, 8.7, 0.859 and 0.116 nM, respectively. Both anti-Scg3 EBP2 and EBP3 hFabs significantly inhibited Scg3-induced proliferation and migration of human umbilical vein endothelial cells in vitro, and alleviated DR vascular leakage and choroidal neovascularization with high efficacy. Paired assays in DR mice revealed that intravitreally injected EBP3 hFab is 26.4% and 10.3% more effective than EBP2 hFab and aflibercept, respectively, for ameliorating DR leakage. In conclusion, this study confirms the markedly improved binding affinities of hFabs compared to mAbs and further identifies EBP3 hFab as the preferred antibody to develop for anti-Scg3 therapy.

Asunto(s)

Inhibidores de la Angiogénesis , Anticuerpos Neutralizantes , Retinopatía Diabética , Células Endoteliales de la Vena Umbilical Humana , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/metabolismo , Retinopatía Diabética/inmunología , Retinopatía Diabética/patología , Humanos , Animales , Ratones , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ratones Endogámicos C57BL , Proteínas de Unión al ARN , Proteínas Adaptadoras Transductoras de Señales

RESUMEN

Arterial endothelial cells (AECs) are the founder cells for intraembryonic haematopoiesis. Here, we report a method for the efficient generation of human haemogenic DLL4+ AECs from pluripotent stem cells (PSC). Time-series single-cell RNA-sequencing reveals the dynamic evolution of haematopoiesis and lymphopoiesis, generating cell types with counterparts present in early human embryos, including stages marked by the pre-haematopoietic stem cell genes MECOM/EVI1, MLLT3 and SPINK2. DLL4+ AECs robustly support lymphoid differentiation, without the requirement for exogenous NOTCH ligands. Using this system, we find IL7 acts as a morphogenic factor determining the fate choice between the T and innate lymphoid lineages and also plays a role in regulating the relative expression level of RAG1. Moreover, we document a developmental pathway by which human RAG1+ lymphoid precursors give rise to the natural killer cell lineage. Our study describes an efficient method for producing lymphoid progenitors, providing insights into their endothelial and haematopoietic ontogeny, and establishing a platform to investigate the development of the human blood system.

Asunto(s)

Hematopoyesis , Linfopoyesis , Humanos , Hematopoyesis/genética , Linfopoyesis/genética , Células Endoteliales/metabolismo , Células Endoteliales/citología , Diferenciación Celular , Linaje de la Célula/genética , Interleucina-7/metabolismo , Interleucina-7/genética , Células Madre Pluripotentes/metabolismo , Células Madre Pluripotentes/citología , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/citología , Hemangioblastos/metabolismo , Hemangioblastos/citología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Análisis de la Célula Individual/métodos , Receptores Notch/metabolismo , Receptores Notch/genética

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales , Proteínas con Dominio LIM , Neoplasias de la Boca , Transducción de Señal , Humanos , Transducción de Señal/efectos de los fármacos , Proteínas con Dominio LIM/metabolismo , Proteínas con Dominio LIM/antagonistas & inhibidores , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas del Citoesqueleto/metabolismo , Proteínas del Citoesqueleto/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/química , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Proliferación Celular/efectos de los fármacos , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Progresión de la Enfermedad , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

NLRP1, the first identified inflammasome-forming sensor, is thought to be involved in cancer, yet its definite function in lung adenocarcinoma (LUAD) remains unclear. Herein, we explored the expression and function of NLRP1 in LUAD. Decreased NLRP1 expression was identified in LUAD, which was associated with a poor prognosis. Overexpression of NLRP1 inhibited tumor growth in vitro and in vivo. Mechanically, this effect was observed regardless of inflammasome activation. Further studies revealed that overexpression of NLRP1 downregulated the phosphorylation of DRP1 and promoted mitochondrial fusion, which was mediated by inhibition of NF-κB activity. NF-κB agonist could neutralize the effect of NLRP1 on mitochondrial dynamics. In addition, LUAD sensitivity to cisplatin was enhanced by decreased mitochondrial fission resulting from up-regulated NLRP1. In conclusion, our findings demonstrated an unexpected role of NLRP1 in LUAD by modulating mitochondrial activities, which provides strong evidence for its potential in LUAD treatment.

Asunto(s)

Adenocarcinoma del Pulmón , Inflamasomas , Neoplasias Pulmonares , Mitocondrias , Proteínas NLR , Humanos , Inflamasomas/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Proteínas NLR/metabolismo , Animales , Mitocondrias/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular Tumoral , Dinámicas Mitocondriales/efectos de los fármacos , Dinámicas Mitocondriales/fisiología , Ratones , Masculino , Proliferación Celular/efectos de los fármacos , Femenino

RESUMEN

Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs) with Methicillin-Resistant S. aureus (MRSA) strains being a major contributor in both community and hospital settings. S. aureus relies on metabolic diversity and a large repertoire of virulence factors to cause disease. This includes α-hemolysin (Hla), an integral player in tissue damage found in various models, including SSTIs. Previously, we identified a role for the Spx adapter protein, YjbH, in the regulation of several virulence factors and as an inhibitor of pathogenesis in a sepsis model. In this study, we found that YjbH is critical for tissue damage during SSTI, and its absence leads to decreased proinflammatory chemokines and cytokines in the skin. We identified no contribution of YjbI, encoded on the same transcript as YjbH. Using a combination of reporters and quantitative hemolysis assays, we demonstrated that YjbH impacts Hla expression and activity both in vitro and in vivo. Additionally, expression of Hla from a non-native promoter reversed the tissue damage phenotype of the ΔyjbIH mutant. Lastly, we identified reduced Agr activity as the likely cause for reduced Hla production in the ΔyjbH mutant. This work continues to define the importance of YjbH in the pathogenesis of S. aureus infection as well as identify a new pathway important for Hla production.

Asunto(s)

Proteínas Bacterianas , Toxinas Bacterianas , Regulación Bacteriana de la Expresión Génica , Proteínas Hemolisinas , Staphylococcus aureus , Transactivadores , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/genética , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/inmunología , Toxinas Bacterianas/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Staphylococcus aureus/patogenicidad , Staphylococcus aureus/inmunología , Staphylococcus aureus/genética , Ratones , Animales , Transactivadores/genética , Transactivadores/metabolismo , Infecciones Cutáneas Estafilocócicas/microbiología , Infecciones Cutáneas Estafilocócicas/inmunología , Infecciones Cutáneas Estafilocócicas/patología , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/inmunología , Piel/microbiología , Piel/patología , Piel/inmunología , Factores de Virulencia/genética , Humanos , Infecciones de los Tejidos Blandos/microbiología , Infecciones de los Tejidos Blandos/inmunología , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Citocinas/metabolismo , Citocinas/inmunología , Citocinas/genética

RESUMEN

The lymphatic system consists of a vessel network lined by specialized lymphatic endothelial cells (LECs) that are responsible for tissue fluid homeostasis and immune cell trafficking. The mechanisms for organ-specific LEC responses to environmental cues are not well understood. We found robust lymphangiogenesis during influenza A virus infection in the adult mouse lung. We show that the number of LECs increases twofold at 7 days post-influenza infection (dpi) and threefold at 21 dpi, and that lymphangiogenesis is preceded by lymphatic dilation. We also show that the expanded lymphatic network enhances fluid drainage to mediastinal lymph nodes. Using EdU labeling, we found that a significantly higher number of pulmonary LECs are proliferating at 7 dpi compared to LECs in homeostatic conditions. Lineage tracing during influenza indicates that new pulmonary LECs are derived from preexisting LECs rather than non-LEC progenitors. Lastly, using a conditional LEC-specific YAP/TAZ knockout model, we established that lymphangiogenesis, fluid transport and the immune response to influenza are independent of YAP/TAZ activity in LECs. These findings were unexpected, as they indicate that YAP/TAZ signaling is not crucial for these processes.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales , Células Endoteliales , Pulmón , Linfangiogénesis , Infecciones por Orthomyxoviridae , Proteínas Señalizadoras YAP , Animales , Proteínas Señalizadoras YAP/metabolismo , Células Endoteliales/metabolismo , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Pulmón/metabolismo , Pulmón/patología , Infecciones por Orthomyxoviridae/metabolismo , Infecciones por Orthomyxoviridae/virología , Infecciones por Orthomyxoviridae/patología , Virus de la Influenza A/fisiología , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patología , Ratones Noqueados , Transducción de Señal , Proliferación Celular , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Ratones Endogámicos C57BL , Factores de Transcripción/metabolismo , Factores de Transcripción/genética

RESUMEN

MicroRNA-27a-5p (miR-27a-5p) was significantly upregulated in dental pulp inflammation, yet its underlying mechanisms remain unclear. This study investigated the effect of miR-27a-5p on the expression of proinflammatory cytokines in human dental pulp cells (hDPCs) stimulated by lipopolysaccharide (LPS). LPS-stimulated hDPCs showed concurrent increases in the expression of miR-27a-5p and proinflammatory cytokines (IL-6, IL-8, and MCP1), and the increased expression was suppressed by NF-κB inhibitor BAY 11-0785. Transfection of the miR-27a-5p mimic downregulated the expression of proinflammatory cytokines, NF-κB activity, and the expression of NF-κB signaling activators (TAB1, IRAK4, RELA, and FSTL1) in LPS-stimulated hDPCs. Luciferase reporter assays revealed that miR-27a-5p bound directly to the 3'-UTR of TAB1. siTAB1 downregulated NF-κB activity and proinflammatory cytokine expression. Downregulation of proinflammatory cytokine expression, NF-κB activity, and NF-κB signaling activator expression (TAB1, IRAK4, and RELA) was also found in LPS-stimulated rat incisor pulp tissue explants following transfection with the miR-27a-5p mimic ex vivo. MiR-27a-5p, whose expression was induced by NF-κB signaling, negatively regulated the synthesis of proinflammatory cytokines via targeting NF-κB signaling. In particular, TAB1, a potent NF-κB activator, was targeted by miR-27a-5p. These results provide insights into the negative regulatory effects of miR-27a-5p, particularly those targeting the TAB1-NF-κB signaling pathway, on pulp inflammation.

Asunto(s)

Citocinas , Pulpa Dental , Lipopolisacáridos , MicroARNs , FN-kappa B , Transducción de Señal , MicroARNs/genética , MicroARNs/metabolismo , Pulpa Dental/citología , Pulpa Dental/metabolismo , Humanos , Lipopolisacáridos/farmacología , Transducción de Señal/efectos de los fármacos , FN-kappa B/metabolismo , Citocinas/metabolismo , Ratas , Animales , Regulación hacia Abajo/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Células Cultivadas , Regiones no Traducidas 3' , Regulación de la Expresión Génica/efectos de los fármacos , Masculino

RESUMEN

Autophagy of glycogen (glycophagy) is crucial for the maintenance of cellular glucose homeostasis and physiology in mammals. STBD1 can serve as an autophagy receptor to mediate glycophagy by specifically recognizing glycogen and relevant key autophagic factors, but with poorly understood mechanisms. Here, we systematically characterize the interactions of STBD1 with glycogen and related saccharides, and determine the crystal structure of the STBD1 CBM20 domain with maltotetraose, uncovering a unique binding mode involving two different oligosaccharide-binding sites adopted by STBD1 CBM20 for recognizing glycogen. In addition, we demonstrate that the LC3-interacting region (LIR) motif of STBD1 can selectively bind to six mammalian ATG8 family members. We elucidate the detailed molecular mechanism underlying the selective interactions of STBD1 with ATG8 family proteins by solving the STBD1 LIR/GABARAPL1 complex structure. Importantly, our cell-based assays reveal that both the STBD1 LIR/GABARAPL1 interaction and the intact two oligosaccharide binding sites of STBD1 CBM20 are essential for the effective association of STBD1, GABARAPL1, and glycogen in cells. Finally, through mass spectrometry, biochemical, and structural modeling analyses, we unveil that STBD1 can directly bind to the Claw domain of RB1CC1 through its LIR, thereby recruiting the key autophagy initiation factor RB1CC1. In all, our findings provide mechanistic insights into the recognitions of glycogen, ATG8 family proteins, and RB1CC1 by STBD1 and shed light on the potential working mechanism of STBD1-mediated glycophagy.

Asunto(s)

Familia de las Proteínas 8 Relacionadas con la Autofagia , Autofagia , Glucógeno , Animales , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/genética , Autofagia/fisiología , Familia de las Proteínas 8 Relacionadas con la Autofagia/metabolismo , Familia de las Proteínas 8 Relacionadas con la Autofagia/genética , Familia de las Proteínas 8 Relacionadas con la Autofagia/química , Sitios de Unión , Cristalografía por Rayos X , Glucógeno/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Asociadas a Microtúbulos/química , Proteínas Asociadas a Microtúbulos/genética , Modelos Moleculares , Unión Proteica

RESUMEN

Background: Bridging integrator 1 (BIN1) gene polymorphism has been reported to play a role in the pathological processes of Alzheimer's disease (AD). Objective: To explore the association of BIN1 loci with neuroinflammation and AD pathology. Methods: Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 495) was the discovery cohort, and Chinese Alzheimer's Biomarker and LifestylE (CABLE, N = 619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model and causal mediation analysis conducted through 10,000 bootstrapped iterations were used to examine the BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia-soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Results: In ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and levels of CSF phosphorylated-tau (P-tau) (pc = 0.017; 0.010, respectively) and total-tau (T-tau) (pc = 0.011; 0.013, respectively). The BIN1 loci were also correlated with CSF sTREM2 levels (pc = 0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of BIN1 loci with P-tau (Proportion of rs7561528 : 20.8%; Proportion of rs744373 : 24.8%) and T-tau (Proportion of rs7561528 : 36.5%; Proportion of rs744373 : 43.9%). The analysis in CABLE study replicated the mediation role of rs7561528. Conclusions: This study demonstrated the correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarkers. Additionally, the link between BIN1 loci and tau pathology was partially mediated by CSF sTREM2.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales , Enfermedad de Alzheimer , Biomarcadores , Glicoproteínas de Membrana , Receptores Inmunológicos , Proteínas Supresoras de Tumor , Proteínas tau , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Femenino , Proteínas Supresoras de Tumor/genética , Masculino , Anciano , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple/genética , Anciano de 80 o más Años , Proteínas Nucleares

RESUMEN

Ovarian cancer, the second most leading cause of gynecologic cancer mortality worldwide, is challenged by chemotherapy resistance, presenting a significant hurdle. Pyroptosis, an inflammation-linked programmed cell death mediated by gasdermins, has been shown to impact chemoresistance when dysregulated. However, the mechanisms connecting pyroptosis to chemotherapy resistance in ovarian cancer are unclear. We found that cytokine receptor-like factor 1 (CRLF1) is a novel component of mTORC2, enhancing AKT Ser473 phosphorylation through strengthening the interaction between AKT and stress-activated protein kinase interacting protein 1 (SIN1), which in turn inhibits the mitogen-activated protein kinase kinase kinase 5 (ASK1)-JNK-caspase-3-gasdermin E pyroptotic pathway and ultimately confers chemoresistance. High CRLF1-expressing tumors showed sensitivity to AKT inhibition but tolerance to cisplatin. Remarkably, overexpression of binding-defective CRLF1 variants impaired AKT-SIN1 interaction, promoting pyroptosis and chemosensitization. Thus, CRLF1 critically regulates chemoresistance in ovarian cancer by modulating AKT/SIN1-dependent pyroptosis. Binding-defective CRLF1 variants could be developed as tumor-specific polypeptide drugs to enhance chemotherapy for ovarian cancer.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales , Resistencia a Antineoplásicos , Diana Mecanicista del Complejo 2 de la Rapamicina , Neoplasias Ováricas , Proteínas Proto-Oncogénicas c-akt , Piroptosis , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Piroptosis/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Línea Celular Tumoral , Animales , Ratones , Cisplatino/farmacología , Cisplatino/uso terapéutico , Ratones Desnudos , Transducción de Señal/efectos de los fármacos

RESUMEN

The IL6-GP130-STAT3 pathway facilitates lung cancer progression and resistance to tyrosine kinase inhibitors. Although glycosylation alters the stability of GP130, its effect on the ligand IL6 remains unclear. We herein find that N-glycosylated IL6, especially at Asn73, primarily stimulates JAK-STAT3 signaling and prolongs STAT3 phosphorylation, whereas N-glycosylation-defective IL6 (deNG-IL6) induces shortened STAT3 activation and alters the downstream signaling preference for the SRC-YAP-SOX2 axis. This signaling shift induces epithelial-mesenchymal transition (EMT) and migration in vitro and metastasis in vivo, which are suppressed by targeted inhibitors and shRNAs against SRC, YAP, and SOX2. Osimertinib-resistant lung cancer cells secrete a large amount of deNG-IL6 through reduced N-glycosyltransferase gene expression, leading to clear SRC-YAP activation. deNG-IL6 contributes to drug resistance, as confirmed by in silico analysis of cellular and clinical transcriptomes and signal expression in patient specimens. Therefore, the N-glycosylation status of IL6 not only affects cell behaviors but also shows promise in monitoring the dynamics of lung cancer evolution.

Asunto(s)

Acrilamidas , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Interleucina-6 , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Factor de Transcripción STAT3 , Humanos , Glicosilación , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Interleucina-6/metabolismo , Interleucina-6/genética , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Inhibidores de Proteínas Quinasas/farmacología , Animales , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Línea Celular Tumoral , Acrilamidas/farmacología , Ratones , Transducción de Señal/efectos de los fármacos , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Compuestos de Anilina/farmacología , Receptor gp130 de Citocinas/metabolismo , Receptor gp130 de Citocinas/genética , Factores de Transcripción SOXB1/metabolismo , Factores de Transcripción SOXB1/genética , Fosforilación , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Familia-src Quinasas/metabolismo , Familia-src Quinasas/genética , Ratones Desnudos , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Metástasis de la Neoplasia , Regulación Neoplásica de la Expresión Génica , Femenino , Indoles , Pirimidinas

RESUMEN

Resveratrol, a potent anticancer bioactive compound, has been shown to trigger apoptosis in numerous cancer cells. Although Notch signaling promotes breast cancer apoptosis, it is unclear whether resveratrol induces apoptosis in MCF-7 cells via influencing the Notch pathway. This study aimed to evaluate the effect of resveratrol on modulating Notch signaling targets and provide critical information for employing resveratrol in breast cancer therapy. Thus, in this study, we have deciphered the effect of resveratrol against three potent genes (Notch1, Jagged1, and DLL4) of the notch signaling pathway. For mechanistic studies, in silico, and in vitro analysis was executed to investigate the apoptotic-inducing potential of resveratrol against three selected oncogenes involved in the progression of breast cancer. Docking analysis revealed the inhibitory potential of resveratrol against all three selected targets of the Notch pathway (Notch1: -5.0; Jagged-1: -5.9; DLL4: -5.8). In vitro, findings further displayed a significant reduction in cell viability in resveratrol-treated MCF-7 cancer cells, which were concomitantly related to the downregulation of Notch-1, Jagged-1, and DLL4. Moreover, the antiproliferative efficacy of resveratrol was correlated with apoptosis and modulation in the expression of Bax, Bcl-2, cyclin D1, CDK4, p21, and caspase-3 activation. Taken together, these experimental findings suggested that apoptotic inducing potential of resveratrol was mediated through a novel mechanism involving suppression of the Notch signaling pathway.

Asunto(s)

Apoptosis , Neoplasias de la Mama , Proteína Jagged-1 , Resveratrol , Transducción de Señal , Humanos , Resveratrol/farmacología , Apoptosis/efectos de los fármacos , Células MCF-7 , Transducción de Señal/efectos de los fármacos , Proteína Jagged-1/metabolismo , Proteína Jagged-1/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Femenino , Receptor Notch1/metabolismo , Receptor Notch1/genética , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Estilbenos/farmacología , Receptores Notch/metabolismo , Receptores Notch/genética , Simulación del Acoplamiento Molecular , Supervivencia Celular/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 3/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética

RESUMEN

Talaromycosis, caused by Talaromyces marneffei (T. marneffei, formerly known as Penicillium marneffei), is an opportunistic invasive mycosis endemic in tropical and subtropical areas of Asia with high mortality rate. Despite various infection models established to study the immunological interaction between T. marneffei and the host, the pathogenicity of this fungus is not yet fully understood. So far, Drosophila melanogaster, a well-established genetic model organism to study innate immunity, has not been used in related research on T. marneffei. In this study, we provide the initial characterization of a systemic infection model of T. marneffei in the D. melanogaster host. Survival curves and fungal loads were tested as well as Toll pathway activation was quantified by RT-qPCR of several antimicrobial peptide (AMP) genes including Drosomycin, Metchnikowin, and Bomanin Short 1. We discovered that whereas most wild-type flies were able to overcome the infection, MyD88 or Toll mutant flies failed to prevent fungal dissemination and proliferation and ultimately succumbed to this challenge. Unexpectedly, the induction of classical Toll pathway activation readouts, Drosomycin and Bomanin Short 1, by live or killed T. marneffei was quite limited in wild-type flies, suggesting that the fungus largely escapes detection by the systemic immune system. This unusual situation of a poor systemic activation of the Toll pathway and a strong susceptibility phenotype of MyD88/Toll might be accounted for by a requirement for this host defence in only specific tissues, a hypothesis that remains to be rigorously tested.

Asunto(s)

Proteínas de Drosophila , Drosophila melanogaster , Factor 88 de Diferenciación Mieloide , Talaromyces , Receptores Toll-Like , Animales , Talaromyces/genética , Talaromyces/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Drosophila melanogaster/microbiología , Drosophila melanogaster/inmunología , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Receptores Toll-Like/metabolismo , Receptores Toll-Like/genética , Micosis/inmunología , Micosis/microbiología , Inmunidad Innata , Transducción de Señal , Antígenos de Diferenciación , Receptores Inmunológicos , Proteínas Adaptadoras Transductoras de Señales