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2.
Curr Pharm Des ; 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31880242

RESUMO

BACKGROUND: Ghrelin (GHRL) is a polypeptide, which can specifically bind to the GHSR. The expression of GHSR has significant differences in human normal and prostate cancer tissues. It is meaningful to find an effective diagnostic method for the diagnosis and prognosis of invasive/neuroendocrine prostate cancer. METHODS: GHRL and GHSR mRNAs level were determined by quantitative real-time polymerase chain reaction in PC tissues. The expression of GHRL and GHSR proteins were assessed respectively by western blot and immunohistochemistry. GHRL polypeptide probe was synthesized through standard solid-phase synthesis of polypeptide, and labeled with Alexa Fluor 660. Confocal microscope was used to capture fluorescence images. Living imaging analysis show tumor areas of different invasiveness in mice models. RESULTS: The level of GHRL and GHSR copy number amplification and mRNA expression were increased in invasive/neuroendocrine prostate cancer, and the protein expression of GHRL and GHSR were similarly boosting in NEPC. The GHRL polypeptide probe could effectively bind to GHSR. In PC3, we found that GHRL probe specifically bind to GHSR on cell membrane and accumulated in cells through internalization after binding. Living imaging in mice models showed that there were different signal intensities in tumor areas of different invasiveness. CONCLUSION: The GHSR and GHRL might be used to the molecular imaging diagnosis for invasive/neuroendocrine prostate cancer in future.

3.
Perspect Psychiatr Care ; 55(3): 372, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30019468

RESUMO

PURPOSE: To advocate an economic way to release inner stress for patients with depression. CONCLUSIONS: Setting off firecrackers has psychological value. It is not merely for fun, but is more an economic and easy behavioral therapy in psychiatric care, even risking a little bit noise and air pollution, especially for patients with depression. PRACTICE IMPLICATIONS: In routine psychiatric care practice, patient with depression were encouraged to set off firecrackers to release their stress.


Assuntos
Terapia Comportamental , Depressão/terapia , Estresse Psicológico/terapia , China , Cultura , Depressão/economia , Explosões , Humanos , Som , Estresse Psicológico/economia
4.
Front Psychiatry ; 9: 525, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405462

RESUMO

About 30% of diabetes patients suffer from varying degrees of depression. Diabetes itself is associated with abnormal carbohydrate and energy metabolism. Whether chronic stress-induced depression-like behavior impacts the metabolome of blood plasma and urine in diabetes is not clear. This study aimed to investigate the effect of chronic stress on metabolome of plasma and urine in spontaneously diabetic Goto-Kakizaki (GK) rats. The GK rats were subjected to 8 weeks' chronic unpredictable mild stress (CUMS) to induce depression-like behavior. Metabolome analysis of blood plasma and urine using liquid chromatography mass spectrometry (LC/MS) was performed. Multivariate data analysis was used to evaluate the data. Behavior and biochemical assay confirmed the successful establishment of CUMS-induced depression-like behavior model in rats. Disturbance of 20 plasma metabolites and 16 urine metabolites were altered in CUMS-induced depression GK rats as compared to control ones. These disturbed metabolites were involved in fatty acid metabolism, sphingolipid metabolism, phenylalanine metabolism, citrate cycle, glycolysis, glutathione metabolism, and nicotinate and nicotinamide metabolism. This study suggest that chronic stress-induced depression-like behavior may further disturb diabetes-itself energy metabolome. The plasma and urine lipid metabolites monitoring may be useful for early detection of depression in patients with diabetes mellitus.

5.
Oncotarget ; 8(44): 76987-76999, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-29100363

RESUMO

The prostate specific antigen (PSA) test is widely used for early diagnosis of prostate cancer (PCa). However, its limited sensitivity has led to over-diagnosis and over-treatment of PCa. Glycosylation alteration is a common phenomenon in cancer development. Different PSA glycan subforms have been proposed as diagnostic markers to better differentiate PCa from benign prostate hyperplasia (BPH). In this study, we purified PSA from expressed prostate secretions (EPS)-urine samples from 32 BPH and 30 PCa patients and provided detailed PSA glycan profiles in Chinese population. We found that most of the PSA glycans from EPS-urine were complex type biantennary glycans. We observed two major patterns in PSA glycan profiles. Overall there was no distinct separation of PSA glycan profiles between BPH and PCa patients. However, we detected a significant increase of glycan FA2 and FM5A2G2S1 in PCa when compared with BPH patients. Furthermore, we observed that the composition of FA2 glycan increased significantly in advanced PCa with Gleason score ≥8, which potentially could be translated to clinic as a marker for aggressive PCa.

6.
Oncotarget ; 8(33): 53948-53958, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28903314

RESUMO

As a newly discovered tumor suppressor, the potential function of PAQR3 in human prostate cancer has not been demonstrated. In this study, we report that PAQR3 is able to inhibit the growth and migration of human prostate cancer cells both in vitro and in vivo. Overexpression of PAQR3 inhibits the proliferation of PC3 and DU145 cells by both MTT and colony formation assays. Consistently, knockdown of PAQR3 enhances the proliferation of these cells. In wound-healing and transwell assays, overexpression of PAQR3 reduces the migration of PC3 and DU145 cells, while PAQR3 knockdown increases it. In a tumor xenograft model, overexpression of PAQR3 suppresses tumor growth of PC3 cells in vivo, while PAQR3 knockdown promotes the tumor growth. PAQR3 is also able to inhibit serum-induced phosphorylation of AKT and ERK in both PC3 and DU145 cells. In addition, PAQR3 suppresses the expression of epithelial-mesenchymal transition (EMT) markers in PC3 cells. Collectively, these data indicate that PAQR3 has a tumor suppressive activity in human prostate cancer cells and may stand out as a potential therapeutic target for prostate cancers.

7.
Appl Opt ; 56(11): 3059-3063, 2017 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-28414363

RESUMO

The fluctuation in the number of signal photoelectrons will cause a range walk error in a Geiger-mode avalanche photodiode (Gm-APD) lidar, which significantly depends on the target intensity. For a nanosecond-pulsed laser, the range walk error of traditional time-of-flight will cause deterioration. A new signal restoration method, based on the Poisson probability response model and the center-of-mass algorithm, is proposed to restrain the range walk error. We obtain a high-precision depth and intensity merged 3D image using this method. The range accuracy is 0.6 cm, and the intensity error is less than 3%.

8.
Nature ; 538(7625): 397-401, 2016 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-27706135

RESUMO

Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically 'rewired' to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.


Assuntos
Chaperonas Moleculares/metabolismo , Complexos Multiproteicos/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Descoberta de Drogas , Feminino , Genes myc/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Chaperonas Moleculares/antagonistas & inibidores , Complexos Multiproteicos/antagonistas & inibidores , Complexos Multiproteicos/química , Neoplasias/tratamento farmacológico , Neoplasias/genética , Especificidade de Órgãos
9.
Appl Opt ; 55(7): 1683-7, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26974630

RESUMO

There exists a range walk error in a Geiger-mode avalanche photodiode (Gm-APD) lidar because of the fluctuation in the number of signal photoelectrons. To restrain this range walk error, we propose a new returning-wave signal processing technique based on the Poisson probability response model and the Gaussian functions fitting method. High-precision depth and intensity information of the target at the distance of 5 m is obtained by a Gm-APD lidar using a 6 ns wide pulsed laser. The experiment results show that the range and intensity precisions are 1.2 cm and 0.015 photoelectrons, respectively.

10.
Opt Express ; 24(5): 5045-5056, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29092333

RESUMO

We investigate the performance of the super-resolving quantum lidar with the entangled coherent states of light in the presence of loss and noise, especially in the noisy case. An exact analytical expression of the output signal has been derived with the binary-outcome photon counting measurements. Numerical results show that the resolution of our scheme with parity detection is √N (N) times enhanced relative to that of the coherent-state strategy with the same (intensity) detection in the lossless and noiseless cases. The influences of phase diffusion on resolution and sensitivity have been analyzed and discussed. It is found that the super-resolution emerges in the whole diffusion rate regions, whereas the super-sensitivity just exists in the high and low diffusion rate regimes. Comparisons are made with the well known N00N states, the results show that the entangled coherent states performs better resolution and sensitivity than those of the N00N scheme in the whole diffusion regimes. In addition, the effects of photon loss on resolution and sensitivity have also been studied. The phase sensitivity can beat the shot noise limit and the resolution is much better than the Rayleigh diffraction limit in the whole loss regions. Finally, the zero-nonzero photon counting measurement gives much worse sensitivity than that of the parity detection, which is just opposite from the case as demonstrated in a recent coherent-light Mach-Zehnder experiment.

11.
ACS Chem Biol ; 9(8): 1698-705, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24934503

RESUMO

Heat shock protein 70 (Hsp70) is a family of proteins with key roles in regulating malignancy. Cancer cells rely on Hsp70 to inhibit apoptosis, regulate senescence and autophagy, and maintain the stability of numerous onco-proteins. Despite these important biological functions in cancer, robust chemical tools that enable the analysis of the Hsp70-regulated proteome in a tumor-by-tumor manner are yet unavailable. Here we take advantage of a recently reported Hsp70 ligand to design and develop an affinity purification chemical toolset for potential use in the investigation of the endogenous Hsp70-interacting proteome in cancer. We demonstrate that these tools lock Hsp70 in complex with onco-client proteins and effectively isolate Hsp70 complexes for identification through biochemical techniques. Using these tools we provide proof-of-concept analyses that glimpse into the complex roles played by Hsp70 in maintaining a multitude of cell-specific malignancy-driving proteins.


Assuntos
Marcadores de Afinidade , Cromatografia de Afinidade/métodos , Proteínas de Choque Térmico HSP70/metabolismo , Neoplasias/metabolismo , Linhagem Celular Tumoral , Proteínas de Choque Térmico HSP70/isolamento & purificação , Humanos , Ligação Proteica
12.
Cell Rep ; 6(6): 1046-1058, 2014 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-24613355

RESUMO

The ability to interconvert terminally differentiated cells could serve as a powerful tool for cell-based treatment of degenerative diseases, including diabetes mellitus. To determine which, if any, adult tissues are competent to activate an islet ß cell program, we performed an in vivo screen by expressing three ß cell "reprogramming factors" in a wide spectrum of tissues. We report that transient intestinal expression of these factors-Pdx1, MafA, and Ngn3 (PMN)-promotes rapid conversion of intestinal crypt cells into endocrine cells, which coalesce into "neoislets" below the crypt base. Neoislet cells express insulin and show ultrastructural features of ß cells. Importantly, intestinal neoislets are glucose-responsive and able to ameliorate hyperglycemia in diabetic mice. Moreover, PMN expression in human intestinal "organoids" stimulates the conversion of intestinal epithelial cells into ß-like cells. Our results thus demonstrate that the intestine is an accessible and abundant source of functional insulin-producing cells.


Assuntos
Células Secretoras de Insulina/citologia , Insulina/biossíntese , Intestinos/citologia , Ilhotas Pancreáticas/citologia , Animais , Diferenciação Celular/fisiologia , Humanos , Células Secretoras de Insulina/metabolismo , Mucosa Intestinal/metabolismo , Ilhotas Pancreáticas/metabolismo , Camundongos , Camundongos Transgênicos
13.
Cell Metab ; 19(2): 259-71, 2014 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-24506867

RESUMO

Pdx1 is a homeobox-containing transcription factor that plays a key role in pancreatic development and adult ß cell function. In this study, we traced the fate of adult ß cells after Pdx1 deletion. As expected, ß-cell-specific removal of Pdx1 resulted in severe hyperglycemia within days. Surprisingly, a large fraction of Pdx1-deleted cells rapidly acquired ultrastructural and physiological features of α cells, indicating that a robust cellular reprogramming had occurred. Reprogrammed cells exhibited a global transcriptional shift that included derepression of the α cell transcription factor MafB, resulting in a transcriptional profile that closely resembled that of α cells. These findings indicate that Pdx1 acts as a master regulator of ß cell fate by simultaneously activating genes essential for ß cell identity and repressing those associated with α cell identity. We discuss the significance of these findings in the context of the emerging notion that loss of ß cell identity contributes to the pathogenesis of type 2 diabetes.


Assuntos
Células Secretoras de Glucagon/metabolismo , Proteínas de Homeodomínio/metabolismo , Células Secretoras de Insulina/metabolismo , Transativadores/metabolismo , Animais , Linhagem Celular , Imunoprecipitação da Cromatina , Proteínas de Homeodomínio/genética , Fator de Transcrição MafB/genética , Fator de Transcrição MafB/metabolismo , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/genética
14.
Carbohydr Polym ; 102: 278-87, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24507283

RESUMO

In this paper, the efficient approach for the synthesis of ß-cyclodextrin (CD) based functional monomers was described. Based on the monovinyl ß-CD monomer (GMA-EDA-CD), a new type poly(AA-co-GMA-EDA-CD) (PCDs) copolymer bearing pendent CD groups was synthesized and used as superplasticizer. Their chemical compositions were characterized by FT-IR, NMR, MALDI-TOF and GPC. The effects of PCDs on dispersion and adsorption in cement mortars were detailed discussed. The results indicated that PCD copolymers behaved excellent dispersion ability and strong retarding effect. PCD2 with molar ratio (%) for monomer (AA:GMA-EDA-CD=80:20) had the best dispersion and dispersion maintaining abilities, which were mainly attributed to the synergistic effects of steric hindrance and electrostatic repulsive force, and the retarding effect of PCD copolymers resulted from steric hindrance repulsion of CD pendants and the large number of hydroxyl groups, which affected the hydration reaction of cement.

15.
Cytokine Growth Factor Rev ; 25(2): 175-83, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24411492

RESUMO

The CBM signalosome plays a pivotal role in mediating antigen-receptor induced NF-κB signaling to regulate lymphocyte functions. The CBM complex forms filamentous structure and recruits downstream signaling components to activate NF-κB. MALT1, the protease component in the CBM complex, cleaves key proteins in the feedback loop of the NF-κB signaling pathway and enhances NF-κB activation. The aberrant activity of the CBM complex has been linked to aggressive lymphoma. Recent years have witnessed dramatic progresses in understanding the assembly mechanism of the CBM complex, and advances in the development of targeted therapy for aggressive lymphoma. Here, we will highlight these progresses and give an outlook on the potential translation of this knowledge from bench to bedside for aggressive lymphoma patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Sinalização CARD/imunologia , Caspases/imunologia , Guanilato Ciclase/imunologia , NF-kappa B/imunologia , Proteínas de Neoplasias/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteína 10 de Linfoma CCL de Células B , Proteínas Adaptadoras de Sinalização CARD/genética , Caspases/genética , Guanilato Ciclase/genética , Linfoma , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas de Neoplasias/genética , Estrutura Terciária de Proteína , Receptores de Antígenos/imunologia , Transdução de Sinais
16.
Chem Biol ; 20(12): 1469-80, 2013 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-24239008

RESUMO

Hsp70s are important cancer chaperones that act upstream of Hsp90 and exhibit independent anti-apoptotic activities. To develop chemical tools for the study of human Hsp70, we developed a homology model that unveils a previously unknown allosteric site located in the nucleotide binding domain of Hsp70. Combining structure-based design and phenotypic testing, we discovered a previously unknown inhibitor of this site, YK5. In cancer cells, this compound is a potent and selective binder of the cytosolic but not the organellar human Hsp70s and has biological activity partly by interfering with the formation of active oncogenic Hsp70/Hsp90/client protein complexes. YK5 is a small molecule inhibitor rationally designed to interact with an allosteric pocket of Hsp70 and represents a previously unknown chemical tool to investigate cellular mechanisms associated with Hsp70.


Assuntos
Sítio Alostérico/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Descoberta de Drogas , Proteínas de Choque Térmico HSP70/química , Proteínas de Choque Térmico HSP90/metabolismo , Fatores de Transcrição de Choque Térmico , Humanos , Modelos Moleculares , Estrutura Terciária de Proteína/efeitos dos fármacos , Homologia Estrutural de Proteína , Fatores de Transcrição/metabolismo
17.
Mol Cell ; 51(6): 766-79, 2013 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-24074955

RESUMO

The CARMA1/Bcl10/MALT1 (CBM) signalosome mediates antigen receptor-induced NF-κB signaling to regulate multiple lymphocyte functions. While CARMA1 and Bcl10 contain caspase recruitment domains (CARDs), MALT1 is a paracaspase with structural similarity to caspases. Here we show that the reconstituted CBM signalosome is a helical filamentous assembly in which substoichiometric CARMA1 nucleates Bcl10 filaments. Bcl10 filament formation is a highly cooperative process whose threshold is sensitized by oligomerized CARMA1 upon receptor activation. In cells, both cotransfected CARMA1/Bcl10 complex and the endogenous CBM signalosome are filamentous morphologically. Combining crystallography, nuclear magnetic resonance, and electron microscopy, we reveal the structure of the Bcl10 CARD filament and the mode of interaction between CARMA1 and Bcl10. Structure-guided mutagenesis confirmed the observed interfaces in Bcl10 filament assembly and MALT1 activation in vitro and NF-κB activation in cells. These data support a paradigm of nucleation-induced signal transduction with threshold response due to cooperativity and signal amplification by polymerization.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Caspases/genética , Guanilato Ciclase/genética , Proteínas de Neoplasias/genética , Transdução de Sinais/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína 10 de Linfoma CCL de Células B , Sítios de Ligação , Proteínas Adaptadoras de Sinalização CARD/química , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspases/química , Caspases/metabolismo , Cristalografia por Raios X , Regulação da Expressão Gênica , Guanilato Ciclase/química , Guanilato Ciclase/metabolismo , Humanos , Células Jurkat , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , NF-kappa B/química , NF-kappa B/genética , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Estrutura Secundária de Proteína
18.
Nat Chem Biol ; 9(11): 677-84, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23995768

RESUMO

Although the Hsp90 chaperone family, comprised in humans of four paralogs, Hsp90α, Hsp90ß, Grp94 and Trap-1, has important roles in malignancy, the contribution of each paralog to the cancer phenotype is poorly understood. This is in large part because reagents to study paralog-specific functions in cancer cells have been unavailable. Here we combine compound library screening with structural and computational analyses to identify purine-based chemical tools that are specific for Hsp90 paralogs. We show that Grp94 selectivity is due to the insertion of these compounds into a new allosteric pocket. We use these tools to demonstrate that cancer cells use individual Hsp90 paralogs to regulate a client protein in a tumor-specific manner and in response to proteome alterations. Finally, we provide new mechanistic evidence explaining why selective Grp94 inhibition is particularly efficacious in certain breast cancers.


Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias/metabolismo , Purinas/farmacologia , Receptor ErbB-2/metabolismo , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Neoplasias/patologia , Purinas/síntese química , Purinas/química , Relação Estrutura-Atividade
19.
Gastroenterology ; 144(7): 1543-53, 1553.e1, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23454691

RESUMO

BACKGROUND & AIMS: The Hippo signaling pathway is a context-dependent regulator of cell proliferation, differentiation, and apoptosis in species ranging from Drosophila to humans. In this study, we investigated the role of the core Hippo kinases-Mst1 and Mst2-in pancreatic development and homeostasis. METHODS: We used a Cre/LoxP system to create mice with pancreas-specific disruptions in Mst1 and Mst2 (Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice), the mammalian orthologs of Drosophila Hippo. We used a transgenic approach to overexpress Yap, the downstream mediator of Hippo signaling, in the developing pancreas of mice. RESULTS: Contrary to expectations, the pancreatic mass of Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice was reduced compared with wild-type mice, largely because of postnatal de-differentiation of acinar cells into duct-like cells. Development of this phenotype coincided with postnatal reactivation of YAP expression. Ectopic expression of YAP during the secondary transition (a stage at which YAP is normally absent) blocked differentiation of the endocrine and exocrine compartments, whereas loss of a single Yap allele reduced acinar de-differentiation. The phenotype of Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice recapitulated cellular and molecular changes observed during chemical-induced pancreatitis in mice. CONCLUSIONS: The mammalian Hippo kinases, and YAP, maintain postnatal pancreatic acinar differentiation in mice.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Pâncreas Exócrino/crescimento & desenvolvimento , Fosfoproteínas/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular , Diferenciação Celular , Proliferação de Células , Camundongos , Camundongos Transgênicos , Pâncreas Exócrino/fisiologia , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais
20.
Cancer Cell ; 22(6): 812-24, 2012 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-23238016

RESUMO

MALT1 cleavage activity is linked to the pathogenesis of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), a chemoresistant form of DLBCL. We developed a MALT1 activity assay and identified chemically diverse MALT1 inhibitors. A selected lead compound, MI-2, featured direct binding to MALT1 and suppression of its protease function. MI-2 concentrated within human ABC-DLBCL cells and irreversibly inhibited cleavage of MALT1 substrates. This was accompanied by NF-κB reporter activity suppression, c-REL nuclear localization inhibition, and NF-κB target gene downregulation. Most notably, MI-2 was nontoxic to mice, and displayed selective activity against ABC-DLBCL cell lines in vitro and xenotransplanted ABC-DLBCL tumors in vivo. The compound was also effective against primary human non-germinal center B cell-like DLBCLs ex vivo.


Assuntos
Linfócitos B/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Animais , Linfócitos B/metabolismo , Caspases/metabolismo , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Proteólise , Proteínas Proto-Oncogênicas c-rel , Ensaios Antitumorais Modelo de Xenoenxerto
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