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1.
Mol Cancer Ther ; 23(1): 3-13, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-37748190

RESUMO

The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their main partner transcription factors, the TEAD1-4 factors, are therefore promising anticancer targets. Because of frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and LATS2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all four TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in subcutaneous xenograft models with human cells and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the sensitivity of mesothelioma models to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has potential to treat multiple Hippo-mutant solid tumor types.


Assuntos
Mesotelioma Maligno , Mesotelioma , Adulto , Humanos , Animais , Camundongos , Via de Sinalização Hippo , Proteínas de Sinalização YAP , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo
2.
Gastroenterology ; 160(3): 847-862, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33127392

RESUMO

BACKGROUND AND AIMS: The Hippo pathway and its downstream effectors YAP and TAZ (YAP/TAZ) are heralded as important regulators of organ growth and regeneration. However, different studies provided contradictory conclusions about their role during regeneration of different organs, ranging from promoting proliferation to inhibiting it. Here we resolve the function of YAP/TAZ during regeneration of the liver, where Hippo's role in growth control has been studied most intensely. METHODS: We evaluated liver regeneration after carbon tetrachloride toxic liver injury in mice with conditional deletion of Yap/Taz in hepatocytes and/or biliary epithelial cells, and measured the behavior of different cell types during regeneration by histology, RNA sequencing, and flow cytometry. RESULTS: We found that YAP/TAZ were activated in hepatocytes in response to carbon tetrachloride toxic injury. However, their targeted deletion in adult hepatocytes did not noticeably impair liver regeneration. In contrast, Yap/Taz deletion in adult bile ducts caused severe defects and delay in liver regeneration. Mechanistically, we showed that Yap/Taz mutant bile ducts degenerated, causing cholestasis, which stalled the recruitment of phagocytic macrophages and the removal of cellular corpses from injury sites. Elevated bile acids activated pregnane X receptor, which was sufficient to recapitulate the phenotype observed in mutant mice. CONCLUSIONS: Our data show that YAP/TAZ are practically dispensable in hepatocytes for liver development and regeneration. Rather, YAP/TAZ play an indirect role in liver regeneration by preserving bile duct integrity and securing immune cell recruitment and function.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colestase/patologia , Regeneração Hepática/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Ductos Biliares/patologia , Tetracloreto de Carbono/administração & dosagem , Tetracloreto de Carbono/toxicidade , Proliferação de Células/genética , Doença Hepática Induzida por Substâncias e Drogas/complicações , Colestase/etiologia , Modelos Animais de Doenças , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Via de Sinalização Hippo , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Proteínas de Sinalização YAP
4.
Science ; 366(6468): 1029-1034, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31754005

RESUMO

The Hippo signaling pathway and its two downstream effectors, the YAP and TAZ transcriptional coactivators, are drivers of tumor growth in experimental models. Studying mouse models, we show that YAP and TAZ can also exert a tumor-suppressive function. We found that normal hepatocytes surrounding liver tumors displayed activation of YAP and TAZ and that deletion of Yap and Taz in these peritumoral hepatocytes accelerated tumor growth. Conversely, experimental hyperactivation of YAP in peritumoral hepatocytes triggered regression of primary liver tumors and melanoma-derived liver metastases. Furthermore, whereas tumor cells growing in wild-type livers required YAP and TAZ for their survival, those surrounded by Yap- and Taz-deficient hepatocytes were not dependent on YAP and TAZ. Tumor cell survival thus depends on the relative activity of YAP and TAZ in tumor cells and their surrounding tissue, suggesting that YAP and TAZ act through a mechanism of cell competition to eliminate tumor cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Colangiocarcinoma/metabolismo , Hepatócitos/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Transativadores/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Colangiocarcinoma/patologia , Via de Sinalização Hippo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas Experimentais/patologia , Melanoma/metabolismo , Melanoma/secundário , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Transativadores/economia , Transativadores/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Carga Tumoral , Proteínas de Sinalização YAP
5.
Cells ; 8(4)2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027317

RESUMO

Inducible cyclization recombinase (Cre) transgenic mouse strains are powerful tools for cell lineage tracing and tissue-specific knockout experiments. However, low efficiency or leaky expression can be important pitfalls. Here, we compared the efficiency and specificity of two commonly used cholangiocyte-specific Cre drivers, the Opn-iCreERT2 and Ck19-CreERT drivers, using a tdTomato reporter strain. We found that Opn-iCreERT2 triggered recombination of the tdTomato reporter in 99.9% of all cholangiocytes while Ck19-CreERT only had 32% recombination efficiency after tamoxifen injection. In the absence of tamoxifen, recombination was also induced in 2% of cholangiocytes for the Opn-iCreERT2 driver and in 13% for the Ck19-CreERT driver. For both drivers, Cre recombination was highly specific for cholangiocytes since recombination was rare in other liver cell types. Toxic liver injury ectopically activated Opn-iCreERT2 but not Ck19-CreERT expression in hepatocytes. However, ectopic recombination in hepatocytes could be avoided by applying a three-day long wash-out period between tamoxifen treatment and toxin injection. Therefore, the Opn-iCreERT2 driver is best suited for the generation of mutant bile ducts, while the Ck19-CreERT driver has near absolute specificity for bile duct cells and is therefore favorable for lineage tracing experiments.


Assuntos
Engenharia Genética/métodos , Queratina-19/metabolismo , Osteopontina/metabolismo , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Ductos Biliares/metabolismo , Linhagem da Célula/efeitos dos fármacos , Feminino , Expressão Gênica/genética , Expressão Gênica/fisiologia , Integrases/biossíntese , Integrases/genética , Integrases/metabolismo , Queratina-19/genética , Queratina-19/fisiologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Transgênicos/genética , Osteopontina/genética , Osteopontina/fisiologia , Proteínas Recombinantes/metabolismo , Tamoxifeno/farmacologia
6.
Proc Natl Acad Sci U S A ; 115(42): 10684-10689, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30257938

RESUMO

The Hippo tumor-suppressor pathway regulates organ growth, cell proliferation, and stem cell biology. Defects in Hippo signaling and hyperactivation of its downstream effectors-Yorkie (Yki) in Drosophila and YAP/TAZ in mammals-result in progenitor cell expansion and overgrowth of multiple organs and contribute to cancer development. Deciphering the mechanisms that regulate the activity of the Hippo pathway is key to understanding its function and for therapeutic targeting. However, although the Hippo kinase cascade and several other upstream inputs have been identified, the mechanisms that regulate Yki/YAP/TAZ activity are still incompletely understood. To identify new regulators of Yki activity, we screened in Drosophila for suppressors of tissue overgrowth and Yki activation caused by overexpression of atypical protein kinase C (aPKC), a member of the apical cell polarity complex. In this screen, we identified mutations in the heterogeneous nuclear ribonucleoprotein Hrb27C that strongly suppressed the tissue defects induced by ectopic expression of aPKC. Hrb27C was required for aPKC-induced tissue growth and Yki target gene expression but did not affect general gene expression. Genetic and biochemical experiments showed that Hrb27C affects Yki phosphorylation. Other RNA-binding proteins known to interact with Hrb27C for mRNA transport in oocytes were also required for normal Yki activity, although they suppressed Yki output. Based on the known functions of Hrb27C, we conclude that Hrb27C-mediated control of mRNA splicing, localization, or translation is essential for coordinated activity of the Hippo pathway.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transativadores/metabolismo , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Proteínas Nucleares/genética , Proteína II de Ligação a Poli(A)/genética , Proteína II de Ligação a Poli(A)/metabolismo , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Transativadores/genética , Proteínas de Sinalização YAP
7.
Nat Commun ; 8(1): 397, 2017 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-28855501

RESUMO

Ubiquitin conjugation signals for selective protein degradation by the proteasome. In eukaryotes, ubiquitin is encoded both as a monomeric ubiquitin unit fused to a ribosomal gene and as multiple ubiquitin units in tandem. The polyubiquitin gene is a unique, highly conserved open reading frame composed solely of tandem repeats, yet it is still unclear why cells utilize this unusual gene structure. Using the Saccharomyces cerevisiae UBI4 gene, we show that this multi-unit structure allows cells to rapidly produce large amounts of ubiquitin needed to respond to sudden stress. The number of ubiquitin units encoded by UBI4 influences cellular survival and the rate of ubiquitin-proteasome system (UPS)-mediated proteolysis following heat stress. Interestingly, the optimal number of repeats varies under different types of stress indicating that natural variation in repeat numbers may optimize the chance for survival. Our results demonstrate how a variable polycistronic transcript provides an evolutionary alternative for gene copy number variation.Eukaryotic cells rely on the ubiquitin-proteasome system for selective degradation of proteins, a process vital to organismal fitness. Here the authors show that the number of repeats in the polyubiquitin gene is evolutionarily unstable within and between yeast species, and that this variability may tune the cell's capacity to respond to sudden environmental perturbations.


Assuntos
Poliubiquitina/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Ubiquitina C/genética , Evolução Biológica , Clonagem Molecular , Variações do Número de Cópias de DNA , Dosagem de Genes , Genes Fúngicos , Proteínas de Fluorescência Verde/metabolismo , Temperatura Alta , Poliubiquitina/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteostase , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Ubiquitina C/metabolismo
8.
Sci Rep ; 5: 7805, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25588812

RESUMO

The brain's impotence to utilize long-chain fatty acids as fuel, one of the dogmas in neuroscience, is surprising, since the nervous system is the tissue most energy consuming and most vulnerable to a lack of energy. Challenging this view, we here show in vivo that loss of the Drosophila carnitine palmitoyltransferase 2 (CPT2), an enzyme required for mitochondrial ß-oxidation of long-chain fatty acids as substrates for energy production, results in the accumulation of triacylglyceride-filled lipid droplets in adult Drosophila brain but not in obesity. CPT2 rescue in glial cells alone is sufficient to restore triacylglyceride homeostasis, and we suggest that this is mediated by the release of ketone bodies from the rescued glial cells. These results demonstrate that the adult brain is able to catabolize fatty acids for cellular energy production.


Assuntos
Drosophila melanogaster/metabolismo , Metabolismo Energético , Neuroglia/metabolismo , Envelhecimento/metabolismo , Sequência de Aminoácidos , Animais , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Carnitina O-Palmitoiltransferase/química , Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimologia , Drosophila melanogaster/genética , Homeostase , Humanos , Larva/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos , Dados de Sequência Molecular , Mutação , Obesidade/patologia , Oxirredução , Fosfolipídeos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Alinhamento de Sequência , Análise de Sobrevida , Triglicerídeos/metabolismo
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