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1.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445664

RESUMO

The target of rapamycin (TOR) protein kinase is an atypical Ser/Thr protein kinase and evolutionally conserved among yeasts, plants, and mammals. TOR has been established as a central hub for integrating nutrient, energy, hormone, and environmental signals in all the eukaryotes. Despite the conserved functions across eukaryotes, recent research has shed light on the multifaceted roles of TOR signaling in plant-specific functional and mechanistic features. One of the most specific features is the involvement of TOR in plant photosynthesis. The recent development of tools for the functional analysis of plant TOR has helped to uncover the involvement of TOR signaling in several steps preceding photoautotrophy and maintenance of photosynthesis. Here, we present recent novel findings relating to TOR signaling and its roles in regulating plant photosynthesis, including carbon nutrient sense, light absorptions, and leaf and chloroplast development. We also provide some gaps in our understanding of TOR function in photosynthesis that need to be addressed in the future.


Assuntos
Fotossíntese/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Autofagia , Proteínas de Plantas/metabolismo , Plantas/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/fisiologia
2.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298987

RESUMO

Limb-girdle muscular dystrophy R1 calpain 3-related (LGMDR1) is an autosomal recessive muscular dystrophy produced by mutations in the CAPN3 gene. It is a rare disease and there is no cure or treatment for the disease while the pathophysiological mechanism by which the absence of calpain 3 provokes the dystrophy in muscles is not clear. However, key proteins implicated in Wnt and mTOR signaling pathways, which regulate muscle homeostasis, showed a considerable reduction in their expression and in their phosphorylation in LGMDR1 patients' muscles. Finally, the administration of tideglusib and VP0.7, ATP non-competitive inhibitors of glycogen synthase kinase 3ß (GSK-3ß), restore the expression and phosphorylation of these proteins in LGMDR1 cells, opening the possibility of their use as therapeutic options.


Assuntos
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Distrofia Muscular do Cíngulo dos Membros/tratamento farmacológico , Proteínas do Tecido Nervoso/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Sítio Alostérico/efeitos dos fármacos , Antígeno CD56/análise , Calpaína/deficiência , Calpaína/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/química , Humanos , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/enzimologia , Proteínas do Tecido Nervoso/química , Fosforilação , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/fisiologia , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/fisiologia , Tiadiazóis/farmacologia , Tiadiazóis/uso terapêutico , Via de Sinalização Wnt/efeitos dos fármacos
3.
J Neurochem ; 159(3): 498-511, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34077553

RESUMO

Akt signaling has been associated with adult neurogenesis in the hippocampal dentate gyrus (DG). We reported cognitive dysfunction in Akt3 knockout (Akt3-KO) mice with the down-regulation of mTOR activation. However, little is known about the effects of Akt3 signaling on hippocampal neurogenesis. Herein, we show that progenitor cells, neuroblasts, and mature newborn neurons in hippocampal DG expressed Akt3 protein. The Akt3 phosphorylation in hippocampal DG was increased after voluntary wheel running for 7 days in wild-type mice (running WT mice), but not in Akt3-KO mice (running Akt3-KO mice). Subsequently, we observed that the proliferation of progenitor cells was suppressed in Akt3-KO mice and the mTOR inhibitor rapamycin-treated mice, whereas enhanced in running WT mice rather than running Akt3-KO mice. Neurite growth of neuroblasts was impaired in Akt3-KO mice and rapamycin-treated mice. In contrast, neither differentiation of progenitor cells nor migrating of newly generated neurons was altered in Akt3-KO mice or running WT mice. The levels of p70S6K and 4EBP1 phosphorylation were declined in Akt3-KO mice and elevated in running WT mice depending on mTOR activation. Furthermore, telomerase activity, telomere length, and expression of telomerase reverse transcriptase (TERT) were decreased in Akt3-KO mice but increased in running WT mice rather than running Akt3-KO mice, which required the mTOR activation. The study provides in vivo evidence that Akt3-mTOR signaling plays an important role in the proliferation of progenitor cells and neurite growth through positive regulated TERT expression and activation of p70S6K and 4EBP1.


Assuntos
Neurogênese/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Animais , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Camundongos , Camundongos Knockout , Células-Tronco Neurais/metabolismo , Neuritos/fisiologia , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Corrida/fisiologia , Telomerase/genética , Telomerase/metabolismo , Encurtamento do Telômero/genética
4.
Biomolecules ; 11(5)2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062764

RESUMO

The mechanistic target of rapamycin (mTOR) is a central regulator of cellular homeostasis that integrates environmental and nutrient signals to control cell growth and survival. Over the past two decades, extensive studies of mTOR have implicated the importance of this protein complex in regulating a broad range of metabolic functions, as well as its role in the progression of various human diseases. Recently, mTOR has emerged as a key signaling molecule in regulating animal entry into a hypometabolic state as a survival strategy in response to environmental stress. Here, we review current knowledge of the role that mTOR plays in contributing to natural hypometabolic states such as hibernation, estivation, hypoxia/anoxia tolerance, and dauer diapause. Studies across a diverse range of animal species reveal that mTOR exhibits unique regulatory patterns in an environmental stressor-dependent manner. We discuss how key signaling proteins within the mTOR signaling pathways are regulated in different animal models of stress, and describe how each of these regulations uniquely contribute to promoting animal survival in a hypometabolic state.


Assuntos
Estresse Fisiológico/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/fisiologia , Adaptação Fisiológica/fisiologia , Animais , Ciclo Celular , Proliferação de Células , Diapausa/fisiologia , Estivação/fisiologia , Hibernação/fisiologia , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Transdução de Sinais/fisiologia
5.
Commun Biol ; 4(1): 788, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172827

RESUMO

Successful specification of the two mouse blastocyst inner cell mass (ICM) lineages (the primitive endoderm (PrE) and epiblast) is a prerequisite for continued development and requires active fibroblast growth factor 4 (FGF4) signaling. Previously, we identified a role for p38 mitogen-activated protein kinases (p38-MAPKs) during PrE differentiation, but the underlying mechanisms have remained unresolved. Here, we report an early blastocyst window of p38-MAPK activity that is required to regulate ribosome-related gene expression, rRNA precursor processing, polysome formation and protein translation. We show that p38-MAPK inhibition-induced PrE phenotypes can be partially rescued by activating the translational regulator mTOR. However, similar PrE phenotypes associated with extracellular signal-regulated kinase (ERK) pathway inhibition targeting active FGF4 signaling are not affected by mTOR activation. These data indicate a specific role for p38-MAPKs in providing a permissive translational environment during mouse blastocyst PrE differentiation that is distinct from classically reported FGF4-based mechanisms.


Assuntos
Blastocisto/fisiologia , Endoderma/citologia , Biossíntese de Proteínas , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , Animais , Diferenciação Celular , Linhagem da Célula , Proteínas de Ligação a DNA/fisiologia , Desenvolvimento Embrionário , Camundongos , Proteínas de Ligação a RNA/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Fatores de Transcrição/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
6.
Theranostics ; 11(13): 6560-6572, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995676

RESUMO

Rationale: Metastasis, the development of secondary malignant growth at a distance from a primary tumor, is the main cause of cancer-associated death. However, little is known about how metastatic cancer cells adapt to and colonize in the new organ environment. Here we sought to investigate the functional mechanism of cholesterol metabolic aberration in colorectal carcinoma (CRC) liver metastasis. Methods: The expression of cholesterol metabolism-related genes in primary colorectal tumors (PT) and paired liver metastases (LM) were examined by RT-PCR. The role of SREBP2-dependent cholesterol biosynthesis pathway in cell growth and CRC liver metastasis were determined by SREBP2 silencing in CRC cell lines and experimental metastasis models including, intra-splenic injection models and liver orthotropic injection model. Growth factors treatment and co-culture experiment were performed to reveal the mechanism underlying the up-regulation of SREBP2 in CRC liver metastases. The in vivo efficacy of inhibition of cholesterol biosynthesis pathway by betulin or simvastatin were evaluated in experimental metastasis models. Results: In the present study, we identify a colorectal cancer (CRC) liver metastasis-specific cholesterol metabolic pathway involving the activation of SREBP2-dependent cholesterol biosynthesis, which is required for the colonization and growth of metastatic CRC cells in the liver. Inhibiting this cholesterol biosynthesis pathway suppresses CRC liver metastasis. Mechanically, hepatocyte growth factor (HGF) from liver environment activates SREBP2-dependent cholesterol biosynthesis pathway by activating c-Met/PI3K/AKT/mTOR axis in CRC cells. Conclusion: Our findings support the notion that CRC liver metastases show a specific cholesterol metabolic aberration. Targeting this cholesterol biosynthesis pathway could be a promising treatment for CRC liver metastasis.


Assuntos
Adenocarcinoma/secundário , Colesterol/biossíntese , Neoplasias Colorretais/metabolismo , Neoplasias Hepáticas/secundário , Adenocarcinoma/metabolismo , Animais , Técnicas de Cocultura , Neoplasias Colorretais/patologia , Vetores Genéticos/farmacologia , Fator de Crescimento de Hepatócito/fisiologia , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Especificidade de Órgãos , Proteínas Proto-Oncogênicas c-met/fisiologia , Interferência de RNA , RNA Interferente Pequeno/genética , Distribuição Aleatória , Transdução de Sinais , Sinvastatina/uso terapêutico , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Serina-Treonina Quinases TOR/fisiologia , Ensaio Tumoral de Célula-Tronco
7.
Dev Biol ; 477: 241-250, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34052210

RESUMO

A critical cell type participating in cardiac outflow tract development is a subpopulation of the neural crest cells, the cardiac neural crest cells (NCCs), whose defect causes a spectrum of cardiovascular abnormalities. Accumulating evidence indicates that mTOR, which belongs to the PI3K-related kinase family and impacts multiple signaling pathways in a variety of contexts, plays a pivotal role for NCC development. Here, we investigated functional roles of mTOR for cardiac neural crest development using several lines of mouse genetic models. We found that disruption of mTOR caused NCC defects and failure of cardiac outflow tract separation, which resulted in a spectrum of cardiac defects including persistent truncus arteriosus, ventricular septal defect and ventricular wall defect. Specifically, mutant neural crest cells showed reduced migration into the cardiac OFT and prematurely exited the cell cycle. A number of critical factors and fundamental signaling pathways, which are important for neural crest and cardiomyocyte development, were impaired. Moreover, actin dynamics was disrupted by mTOR deletion. Finally, by phenotyping the neural crest Rptor and Rictor knockout mice respectively, we demonstrate that mTOR acts principally through the mTORC1 pathway for cardiac neural crest cells. Altogether, these data established essential roles of mTOR for cardiac NCC development and imply that dysregulation of mTOR in NCCs may underline a spectrum of cardiac defects.


Assuntos
Anormalidades Cardiovasculares/genética , Coração/embriologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Miocárdio/metabolismo , Crista Neural/embriologia , Serina-Treonina Quinases TOR/fisiologia , Animais , Células Cultivadas , Deleção de Genes , Redes e Vias Metabólicas , Camundongos , Crista Neural/metabolismo , Serina-Treonina Quinases TOR/genética
8.
Adv Cancer Res ; 150: 335-363, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33858600

RESUMO

Cellular senescence, cancer and aging are highly interconnected. Among many important molecular machines that lie at the intersection of this triad, the mechanistic (formerly mammalian) target of rapamycin (mTOR) is a central regulator of cell metabolism, proliferation, and survival. The mTOR signaling cascade is essential to maintain cellular homeostasis in normal biological processes or in response to stress, and its dysregulation is implicated in the progression of many disorders, including age-associated diseases. Accordingly, the pharmacological implications of mTOR inhibition using rapamycin or others rapalogs span the treatment of various human diseases from immune disorders to cancer. Importantly, rapamycin is one of the only known pan-species drugs that can extend lifespan. The molecular and cellular mechanisms explaining the phenotypic consequences of mTOR are vast and heavily studied. In this review, we will focus on the potential role of mTOR in the context of cellular senescence, a tumor suppressor mechanism and a pillar of aging. We will explore the link between senescence, autophagy and mTOR and discuss the opportunities to exploit senescence-associated mTOR functions to manipulate senescence phenotypes in age-associated diseases and cancer treatment.


Assuntos
Senescência Celular/genética , Terapia de Alvo Molecular/métodos , Serina-Treonina Quinases TOR/fisiologia , Envelhecimento/fisiologia , Animais , Antineoplásicos/uso terapêutico , Autofagia/fisiologia , Humanos , Terapia de Alvo Molecular/tendências , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Inibidores de Proteínas Quinases/uso terapêutico
9.
Hum Cell ; 34(2): 698-699, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33527306

RESUMO

The current COVID-19 is one of the deadliest pandemics in recent decades. In the lack of a specific treatment for this novel infection, knowing the role of cell signaling pathways in the pathogenesis of this infection could be useful in finding effective drugs against this disease. The mammalian or mechanistic target of rapamycin (mTOR) is an important cell signaling pathway that has important role in the regulation of cell growth, protein synthesis, and metabolism in reactance to upstream signals in both pathological and normal physiological conditions. Recently, some researchers have suggested the therapeutic potential of mTOR inhibitors such as rapamycin against COVID-19. However, it is important to consider the role of activation of this pathway in controlling immune system response against viral activity in drug repositioning of rapamycin and other mTOR inhibitors in SARS-CoV-2 infection.


Assuntos
COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Sistema Imunitário/imunologia , Transdução de Sinais/genética , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/fisiologia , COVID-19/imunologia , Humanos , Transdução de Sinais/fisiologia
10.
Obes Rev ; 22(4): e13221, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33569904

RESUMO

Obesity and obesogenic comorbidities have been associated with COVID-19 susceptibility and mortality. However, the mechanism of such correlations requires an in-depth understanding. Overnutrition/excess serum amino acid profile during obesity has been linked with inflammation and reprogramming of translational machinery through hyperactivation of amino acid sensor mammalian target of rapamycin (mTOR), which is exploited by SARS-CoV-2 for its replication. Conversely, we have shown that the activation of general control nonderepressible 2 (GCN2)-dependent amino acid starvation sensing pathway suppresses intestinal inflammation by inhibiting the production of reactive oxygen species (ROS) and interleukin-1 beta (IL-1ß). While activation of GCN2 has shown to mitigate susceptibility to dengue infection, GCN2 deficiency increases viremia and inflammation-associated pathologies. These findings reveal that the amino acid sensing pathway plays a significant role in controlling inflammation and viral infections. The current fact is that obesity/excess amino acids/mTOR activation aggravates COVID-19, and it might be possible that activation of amino acid starvation sensor GCN2 has an opposite effect. This article focuses on the amino acid sensing pathways through which host cells sense the availability of amino acids and reprogram the host translation machinery to mount an effective antiviral response. Besides, how SARS-CoV-2 hijack and exploit amino acid sensing pathway for its replication and pathogenesis is also discussed.


Assuntos
Aminoácidos/metabolismo , COVID-19/epidemiologia , N-Acetilexosaminiltransferases/fisiologia , Obesidade/epidemiologia , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/fisiopatologia , Comorbidade , Humanos , Inflamação , Obesidade/fisiopatologia , Biossíntese de Proteínas/fisiologia , SARS-CoV-2/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Replicação Viral/fisiologia
11.
Oncol Rep ; 45(1): 107-118, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33155663

RESUMO

Intrahepatic cholangiocarcinoma (ICC) is a type of cancer that is difficult to cure; chemoresistance of cholangiocarcinoma cells affect the prognosis of patients who cannot be treated with surgery. The mechanism underlying this chemoresistance remains unknown. Mesenchymal stem cells (MSCs) are known to be important components of the tumor microenvironment. In the present study, a large number of MSCs were observed to infiltrate the tumor sites of ICC; thus, MSCs were isolated from ICC tumor tissues. It was revealed that herpesvirus entry mediator (HVEM) was overexpressed in ICC­MSCs. The present study then investigated the role of HVEM­overexpressing MSCs in the chemoresistance of cholangiocarcinoma cells. It was demonstrated that HVEM­overexpressing MSCs could support cell survival of chemotherapeutic cholangiocarcinoma cells and inhibited their apoptosis. Further investigations revealed that HVEM­overexpressing MSCs could secrete IL­6 and also activated AMPK/mTOR­dependent autophagy of cholangiocarcinoma cells. Thus, it was concluded that ICC­MSC­induced autophagy is the primary cause of chemoresistance in ICC.


Assuntos
Autofagia/fisiologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Células-Tronco Mesenquimais/fisiologia , Proteínas Quinases Ativadas por AMP/fisiologia , Adulto , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Interleucina-6/fisiologia , Masculino , Pessoa de Meia-Idade , Membro 14 de Receptores do Fator de Necrose Tumoral/fisiologia , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/fisiologia
12.
Clin Nutr ; 40(4): 2025-2034, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33008652

RESUMO

BACKGROUND & AIMS: Our previous study found that platelet counts were positively associated with body fat percentage in human. In the present study, we conducted a reverse translational study to explore the role of platelets in modulating pre-adipocyte proliferation in mice. METHODS: Mouse pre-adipocyte cell line (3T3-L1) and human pre-adipocytes harvested from female subcutaneous fat were used. Pre-adipocytes were co-cultured with platelets or platelet releasate, which were isolated from mice or humans. The cell viability and proliferative ability of the pre-adipocytes were examined by MTT and flow cytometry assays. Western blotting analysis was used to determine the phosphorylation levels of proteins in the mTOR pathway. RESULTS: The number of platelets in the adipose tissues from obese mice was significantly higher than that from lean mice. Platelets and collagen-activated platelet releasate stimulated the proliferation of human pre-adipocytes and 3T3-L1 cells in vitro. Besides, platelets from obese mice were more potent in stimulating pre-adipocyte proliferation than those from lean control mice. Mechanistically, platelets enhanced pre-adipocyte proliferation through the acceleration of cell cycle progression from G0/G1 to S phase cell cycle progression. At the molecular level, platelets promoted pre-adipocyte proliferation through mTOR pathway-mediated upregulation of cyclin D1 expression. CONCLUSION: In conclusion, platelets and platelet releasate play an important role in the proliferation of pre-adipocytes. Our study may provide new clues and the molecular mechanism of the causal pathways between platelets and body fat to explain the finding we observed in population study.


Assuntos
Adipócitos/fisiologia , Tecido Adiposo/fisiopatologia , Plaquetas/fisiologia , Células 3T3-L1 , Tecido Adiposo/patologia , Animais , Apoptose , Plaquetas/patologia , Comunicação Celular , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Ciclina D1/fisiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/patologia , Obesidade/fisiopatologia , Contagem de Plaquetas , Organismos Livres de Patógenos Específicos , Gordura Subcutânea , Serina-Treonina Quinases TOR/fisiologia
13.
J Mol Neurosci ; 71(1): 101-111, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32557145

RESUMO

This study was designed to investigate the effect of naringin in oxygen-glucose deprivation/reoxygenation (OGD/R) model and its mechanism. The target gene of naringin and the enriched pathways of the gene were searched and identified using bioinformatics analysis. Then OGD/R model was built using PC12 cells, after which the cells were treated with different concentrations of naringin. Subsequently, cell proliferation and apoptosis were evaluated by cell counting kit-8 (CCK-8) and flow cytometry assays, respectively. Meanwhile, the expression of NFKB1 in PC12 cells underwent OGD/R-induced injury was detected by qRT-PCR, while apoptosis-related and pathway-related proteins were checked by Western blot. DCF-DA kit was utilized to measure the level of ROS. Our results revealed that NFKB1, which was upregulated in MACO rats and OGD/R-treated PC12 cells, was a target gene of naringin. Naringin could alleviate OGD/R-induced injury via promoting the proliferation, and repressing the apoptosis of PC12 cells through regulating the expression of NFKB1 and apoptosis-associated proteins and ROS level. Besides, the depletion of NFKB1 was positive to cell proliferation but negative to cell apoptosis. Moreover, the depletion of NFKB1 enhanced the influences of naringin on cell proliferation and apoptosis as well as the expression of apoptosis-related proteins and ROS level. Western blotting indicated that both naringin treatment and depletion of NFKB1 could increase the expression of HIF-1α, p-AKT, and p-mTOR compared with OGD/R group. What's more, treatment by naringin and si-NFKB1 together could significantly increase these effects. Nevertheless, the expression of AKT and mTOR among each group was almost not changed. In conclusion, naringin could prevent the OGD/R-induced injury in PC12 cells in vitro by targeting NFKB1 and regulating HIF-1α/AKT/mTOR-signaling pathway, which might provide novel ideas for the therapy of cerebral ischemia-reperfusion (I/R) injury.


Assuntos
Flavanonas/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Subunidade p50 de NF-kappa B/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/fisiologia , Traumatismo por Reperfusão/prevenção & controle , Serina-Treonina Quinases TOR/fisiologia , Animais , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Flavanonas/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Glucose/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/genética , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/fisiologia , Oxigênio/farmacologia , Células PC12 , Fitoterapia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Proteína X Associada a bcl-2/biossíntese , Proteína X Associada a bcl-2/genética
14.
Transl Res ; 232: 13-36, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33352298

RESUMO

As the world navigates the coronavirus disease 2019 (COVID-19) pandemic, there is a growing need to assess its impact in patients with autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE). Patients with SLE are a unique population when considering the risk of contracting COVID-19 and infection outcomes. The use of systemic glucocorticoids and immunosuppressants, and underlying organ damage from SLE are potential susceptibility factors. Most patients with SLE have evidence of high type I interferon activity, which may theoretically act as an antiviral line of defense or contribute to the development of a deleterious hyperinflammatory response in COVID-19. Other immunopathogenic mechanisms of SLE may overlap with those described in COVID-19, thus, studies in SLE could provide some insight into immune responses occurring in severe cases of the viral infection. We reviewed the literature to date on COVID-19 in patients with SLE and provide an in-depth review of current research in the area, including immune pathway activation, epidemiology, clinical features, outcomes, and the psychosocial impact of the pandemic in those with autoimmune disease.


Assuntos
COVID-19/etiologia , Lúpus Eritematoso Sistêmico/complicações , SARS-CoV-2 , Anticorpos Antifosfolipídeos/imunologia , COVID-19/epidemiologia , COVID-19/imunologia , Proteínas do Sistema Complemento/fisiologia , Armadilhas Extracelulares/fisiologia , Acesso aos Serviços de Saúde , Humanos , Interferon Tipo I/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Serina-Treonina Quinases TOR/fisiologia
15.
Oncogene ; 40(4): 746-762, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33247204

RESUMO

Leukemias are routinely sub-typed for risk/outcome prediction and therapy choice using acquired mutations and chromosomal rearrangements. Down syndrome acute lymphoblastic leukemia (DS-ALL) is characterized by high frequency of CRLF2-rearrangements, JAK2-mutations, or RAS-pathway mutations. Intriguingly, JAK2 and RAS-mutations are mutually exclusive in leukemic sub-clones, causing dichotomy in therapeutic target choices. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. On primary clinical DS-ALL samples, we show that wtRAS-activation is an obligatory consequence of mutated/hyperphosphorylated JAK2. We further prove that CRLF2-ligand TSLP boosts the direct binding of active PTPN11 to wtRAS, providing the molecular mechanism for the wtRAS activation. Pre-inhibition of RAS or PTPN11, but not of PI3K or JAK-signaling, prevented TSLP-induced RAS-GTP boost. Cytotoxicity assays on primary clinical DS-ALL samples demonstrated that, regardless of mutation status, high-risk leukemic cells could only be killed using RAS-inhibitor or PTPN11-inhibitor, but not PI3K/JAK-inhibitors, suggesting a unified treatment target for up to 80% of DS-ALL. Importantly, protein activities-based principal-component-analysis multivariate clusters analyzed for independent outcome prediction using Cox proportional-hazards model showed that protein-activity (but not mutation-status) was independently predictive of outcome, demanding a paradigm-shift in patient-stratification strategy for precision therapy in high-risk ALL.


Assuntos
Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas ras/fisiologia , Animais , Citocinas/fisiologia , Humanos , Janus Quinase 2/genética , Janus Quinase 2/fisiologia , Camundongos , Fosfatidilinositol 3-Quinases/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteína Tirosina Fosfatase não Receptora Tipo 11/fisiologia , Receptores de Citocinas/genética , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Proteínas ras/antagonistas & inibidores , Proteínas ras/genética
16.
Nucleic Acids Res ; 49(1): 458-478, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33332560

RESUMO

The mammalian target of rapamycin (mTOR) is a critical regulator of cell growth, integrating multiple signalling cues and pathways. Key among the downstream activities of mTOR is the control of the protein synthesis machinery. This is achieved, in part, via the co-ordinated regulation of mRNAs that contain a terminal oligopyrimidine tract (TOP) at their 5'ends, although the mechanisms by which this occurs downstream of mTOR signalling are still unclear. We used RNA-binding protein (RBP) capture to identify changes in the protein-RNA interaction landscape following mTOR inhibition. Upon mTOR inhibition, the binding of LARP1 to a number of mRNAs, including TOP-containing mRNAs, increased. Importantly, non-TOP-containing mRNAs bound by LARP1 are in a translationally-repressed state, even under control conditions. The mRNA interactome of the LARP1-associated protein PABPC1 was found to have a high degree of overlap with that of LARP1 and our data show that PABPC1 is required for the association of LARP1 with its specific mRNA targets. Finally, we demonstrate that mRNAs, including those encoding proteins critical for cell growth and survival, are translationally repressed when bound by both LARP1 and PABPC1.


Assuntos
Autoantígenos/fisiologia , Proteína I de Ligação a Poli(A)/fisiologia , Polirribossomos/metabolismo , Biossíntese de Proteínas/fisiologia , RNA Mensageiro/metabolismo , Ribonucleoproteínas/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Regiões 5' não Traduzidas/genética , Autoantígenos/genética , Regulação da Expressão Gênica , Genes Reporter , Células HeLa , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Naftiridinas/farmacologia , Mutação Puntual , Biossíntese de Proteínas/genética , Interferência de RNA , RNA Mensageiro/genética , Proteínas de Ligação a RNA/isolamento & purificação , Proteínas de Ligação a RNA/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Ribonucleoproteínas/genética
17.
J Cancer Res Clin Oncol ; 147(2): 499-505, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33225417

RESUMO

PURPOSE: There is not much progress in the treatment for lung squamous cell carcinoma LSCC in the past few years. Rapamycin Rapa, an inhibitor of mammalian target of rapamycin mTOR, has exhibited antitumor efficacy in a variety of malignant tumors. It has recently been reported that Rapamycin can induce autophagy signaling pathway in lung cancer and Glypican-3GPC3 can promote the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling pathway. The aim of this study is to investigate the mechanisms of rapamycin's antitumor efficacy in relation to GPC3/Wnt/ß-catenin pathway and autophagy in LSCC. METHODS: SK-MES-1 cells, a LSCC cell line, were treated with various concentrations of rapamycin with or without Glypican-3 GPC3-targeting siRNA. SK-MES-1 cell proliferation was determined by MTT assay. Protein expression levels of GPC3, ß-catenin, Beclin-1 were checked via western blotting. We established the xenograft mice model to investigate the suppression effect of rapamycin on LSCC. In addition, we further testified the metabolism protein of autophagy process using the xenograft tumor tissue. RESULTS: Rapamycin could inhibit the SK-MES-1 cell proliferation in a concentration-dependent manner both in vitro and in vivo by decreasing the GPC3 expression and downregulating the glypican-3/Wnt/ß-catenin signaling pathway. In addition, we found that GPC3 silencing can activate the glypican-3/Wnt/ß-catenin pathway and autophagy, which contribute to the suppression of tumor growth both in vitro and in vivo. CONCLUSION: Rapamycin suppresses the growth of lung cancer through down-regulating glypican-3/Wnt/ß-catenin signaling, which mediates with activation of autophagy. This study suggests GPC3 is a new promising target for rapamycin in the treatment of lung cancer.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Glipicanas/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Sirolimo/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Feminino , Glipicanas/fisiologia , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/fisiologia , Via de Sinalização Wnt/fisiologia , beta Catenina/fisiologia
19.
Blood ; 137(5): 661-677, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33197925

RESUMO

A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982).


Assuntos
Acetamidas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Isoindóis/farmacologia , Leucemia Mieloide Aguda/patologia , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Piperidonas/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Acetamidas/uso terapêutico , Animais , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Humanos , Isoindóis/uso terapêutico , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Moleculares , Células-Tronco Neoplásicas/enzimologia , Proteína do Fator Nuclear 45/fisiologia , Proteínas do Fator Nuclear 90/fisiologia , Fatores de Terminação de Peptídeos/metabolismo , Piperidonas/uso terapêutico , Complexo de Endopeptidases do Proteassoma/metabolismo , Conformação Proteica , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteólise , Bibliotecas de Moléculas Pequenas , Estresse Fisiológico , Serina-Treonina Quinases TOR/fisiologia , Células U937 , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Int J Mol Sci ; 21(21)2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33158137

RESUMO

The target of rapamycin (TOR) is an evolutionarily-conserved serine/threonine kinase that senses and integrates signals from the environment to coordinate developmental and metabolic processes. TOR senses nutrients, hormones, metabolites, and stress signals to promote cell and organ growth when conditions are favorable. However, TOR is inhibited when conditions are unfavorable, promoting catabolic processes such as autophagy. Autophagy is a macromolecular degradation pathway by which cells degrade and recycle cytoplasmic materials. TOR negatively regulates autophagy through phosphorylation of ATG13, preventing activation of the autophagy-initiating ATG1-ATG13 kinase complex. Here we review TOR complex composition and function in photosynthetic and non-photosynthetic organisms. We also review recent developments in the identification of upstream TOR activators and downstream effectors of TOR. Finally, we discuss recent developments in our understanding of the regulation of autophagy by TOR in photosynthetic organisms.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Autofagia/genética , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Animais , Proteínas Relacionadas à Autofagia/genética , Humanos , Fosforilação , Transdução de Sinais/fisiologia , Fatores de Transcrição/fisiologia
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