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1.
Trends Biochem Sci ; 48(5): 450-462, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36709077

RESUMEN

The Hippo signaling pathway inhibits the activity of the oncogenic YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)-TEAD (TEA/ATTS domain) transcriptional complex. In cancers, inactivating mutations in upstream Hippo components and/or enhanced activity of YAP/TAZ and TEAD have been observed. The activity of this transcriptional complex can be effectively inhibited by targeting the TEAD family of transcription factors. The development of TEAD inhibitors has been driven by the discovery that TEAD has druggable hydrophobic pockets, and is currently at the clinical development stage. Three small molecule TEAD inhibitors are currently being tested in Phase I clinical trials. In this review, we highlight the role of TEADs in cancer, discuss various avenues through which TEAD activity can be inhibited, and outline the opportunities for the administration of TEAD inhibitors.


Asunto(s)
Neoplasias , Factores de Transcripción de Dominio TEA , Humanos , Factores de Transcripción/metabolismo , Neoplasias/tratamiento farmacológico , Vía de Señalización Hippo
2.
Theranostics ; 10(8): 3622-3635, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32206112

RESUMEN

The transcriptional co-regulators YAP and TAZ pair primarily with the TEAD family of transcription factors to elicit a gene expression signature that plays a prominent role in cancer development, progression and metastasis. YAP and TAZ endow cells with various oncogenic traits such that they sustain proliferation, inhibit apoptosis, maintain stemness, respond to mechanical stimuli, engineer metabolism, promote angiogenesis, suppress immune response and develop resistance to therapies. Therefore, inhibiting YAP/TAZ- TEAD is an attractive and viable option for novel cancer therapy. It is exciting to know that many drugs already in the clinic restrict YAP/TAZ activities and several novel YAP/TAZ inhibitors are currently under development. We have classified YAP/TAZ-inhibiting drugs into three groups. Group I drugs act on the upstream regulators that are stimulators of YAP/TAZ activities. Many of the Group I drugs have the potential to be repurposed as YAP/TAZ indirect inhibitors to treat various solid cancers. Group II modalities act directly on YAP/TAZ or TEADs and disrupt their interaction; targeting TEADs has emerged as a novel option to inhibit YAP/TAZ, as TEADs are major mediators of their oncogenic programs. TEADs can also be leveraged on using small molecules to activate YAP/TAZ-dependent gene expression for use in regenerative medicine. Group III drugs focus on targeting one of the oncogenic downstream YAP/TAZ transcriptional target genes. With the right strategy and impetus, it is not far-fetched to expect a repurposed group I drug or a novel group II drug to combat YAP and TAZ in cancers in the near future.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas de Unión al ADN/antagonistas & inhibidores , Neoplasias/terapia , Transactivadores/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/farmacología , Antineoplásicos/farmacología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Proteínas de Unión al ADN/farmacología , Diseño de Fármacos , Vía de Señalización Hippo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Oncogénicas/efectos de los fármacos , Proteínas Oncogénicas/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Transactivadores/farmacología , Factores de Transcripción/metabolismo , Factores de Transcripción/farmacología , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAP
3.
Gene ; 377: 46-55, 2006 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-16781089

RESUMEN

Angiotensin-converting enzyme 2 (ACE2), a newly identified member in the renin-angiotensin system (RAS), acts as a negative regulator of ACE. It is mainly expressed in cardiac blood vessels and the tubular epithelia of kidneys and abnormal expression has been implicated in diabetes, hypertension and heart failure. The mechanism and physiological function of this zinc metallopeptidase in mammals are not yet fully understood. Non-mammalian vertebrate models offer attractive and simple alternatives that could facilitate the exploration of ACE2 function. In this paper we report the in silico analysis of Ace2 genes from the Gallus (chicken), Xenopus (frog), Fugu and Tetraodon (pufferfish) genome assembly databases, and from the Danio (zebrafish) cDNA library. Exon ambiguities of Danio and Xenopus Ace2s were resolved by RT-PCR and 3'RACE. Analyses of the exon-intron structures, alignment, phylogeny and hydrophilicity plots, together with the conserved synteny among these vertebrates, support the orthologous relationship between mammalian and non-mammalian ACE2s. The putative promoters of Ace2 from human, Tetraodon and Xenopus tropicalis drove the expression of enhanced green fluorescent protein (EGFP) specifically in the heart tissue of transgenic Xenopus thus making it a suitable model for future functional genomic studies. Additionally, the search for conserved cis-elements resulted in the discovery of WGATAR motifs in all the putative Ace2 promoters from 7 different animals, suggesting a possible role of GATA family transcriptional factors in regulating the expression of Ace2.


Asunto(s)
Peptidil-Dipeptidasa A/genética , Vertebrados/genética , Enzima Convertidora de Angiotensina 2 , Animales , Animales Modificados Genéticamente , Secuencia de Bases , Pollos/genética , Mapeo Cromosómico , ADN Complementario/genética , Exones , Proteínas Fluorescentes Verdes/genética , Humanos , Intrones , Datos de Secuencia Molecular , Peptidil-Dipeptidasa A/química , Filogenia , Regiones Promotoras Genéticas , Proteínas Recombinantes/genética , Takifugu/genética , Tetraodontiformes/genética , Xenopus/genética , Pez Cebra/genética
4.
J Cell Sci ; 118(Pt 6): 1209-22, 2005 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-15728249

RESUMEN

The TRAPP complex identified in yeast regulates vesicular transport in the early secretory pathway. Although some components of the TRAPP complex are structurally conserved in mammalian cells, the function of the mammalian components has not been examined. We describe our biochemical and functional analysis of mammalian Bet3, the most conserved component of the TRAPP complex. Bet3 mRNA is ubiquitously expressed in all tissues. Antibodies raised against recombinant Bet3 specifically recognize a protein of 22 kDa. In contrast to yeast Bet3p, the majority of Bet3 is present in the cytosol. To investigate the possible involvement of Bet3 in transport events in mammalian cells, we utilized a semi-intact cell system that reconstitutes the transport of the envelope glycoprotein of vesicular stomatitis virus (VSV-G) from the ER to the Golgi apparatus. In this system, antibodies against Bet3 inhibit transport in a dose-dependent manner, and cytosol that is immunodepleted of Bet3 is also defective in this transport. This defect can be rescued by supplementing the Bet3-depleted cytosol with recombinant GST-Bet3. We also show that Bet3 acts after COPII but before Rab1, alpha-SNAP and the EGTA-sensitive stage during ER-Golgi transport. Gel filtration analysis demonstrates that Bet3 exists in two distinct pools in the cytosol, the high-molecular-weight pool may represent the TRAPP complex, whereas the other probably represents the monomeric Bet3.


Asunto(s)
Retículo Endoplásmico/metabolismo , Aparato de Golgi/metabolismo , Proteínas de la Membrana/fisiología , Proteínas de Transporte Vesicular/fisiología , Secuencia de Aminoácidos , Animales , Transporte Biológico , Northern Blotting , Vesículas Cubiertas por Proteínas de Revestimiento/química , Cromatografía en Gel , Citosol/metabolismo , Relación Dosis-Respuesta a Droga , Ácido Egtácico/química , Escherichia coli/metabolismo , Células HeLa , Humanos , Riñón/metabolismo , Hígado/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Microscopía Fluorescente , Datos de Secuencia Molecular , Proteínas de Complejo Poro Nuclear , Estructura Terciaria de Proteína , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes/química , Proteínas de Saccharomyces cerevisiae , Homología de Secuencia de Aminoácido , Proteínas Solubles de Unión al Factor Sensible a la N-Etilmaleimida , Fracciones Subcelulares/metabolismo , Distribución Tisular , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/metabolismo , Proteínas del Envoltorio Viral/metabolismo , Proteínas de Unión al GTP rab1/metabolismo
5.
Mol Biol Cell ; 13(12): 4317-32, 2002 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-12475955

RESUMEN

We present evidence to suggest the existence of a regulatory pathway for the Golgi apparatus to modulate the spatial positioning of otherwise distantly located lysosomes. Rab34, a new member of the Rab GTPase family, is associated primarily with the Golgi apparatus. Expression of wild-type or GTP-restricted but not GDP-restricted versions of Rab34 causes spatial redistribution of lysosomes from the periphery to the peri-Golgi region. The regulation of lysosomal positioning by Rab34 depends on its association with the membrane mediated by prenylation and its direct interaction with Rab-interacting lysosomal protein (RILP). This biological activity, mediated by Rab34-RILP interaction, is dependent on Lys82 in the switch I region. Our results have uncovered a novel mechanism for the Golgi apparatus to regulate the spatial distribution of another organelle.


Asunto(s)
Proteínas Portadoras/metabolismo , Aparato de Golgi/metabolismo , Lisosomas/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Proteínas de Unión al GTP rab/fisiología , Proteínas Adaptadoras Transductoras de Señales , Secuencia de Aminoácidos , Animales , Axones , Secuencia de Bases , Células Cultivadas , Clonación Molecular , Citoesqueleto/metabolismo , ADN Complementario/metabolismo , Técnica del Anticuerpo Fluorescente Indirecta , Glutatión Transferasa/metabolismo , Células HeLa , Humanos , Lisina/química , Ratones , Microscopía Fluorescente , Modelos Genéticos , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Proteínas de Plantas , Unión Proteica , Ratas , Homología de Secuencia de Aminoácido , Transfección , Técnicas del Sistema de Dos Híbridos
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