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1.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208772

RESUMO

Inflammation is increasingly recognized as a critical mediator of angiogenesis, and unregulated angiogenic responses often involve human diseases. The importance of regulating angiogenesis in inflammatory diseases has been demonstrated through some successful cases of anti-angiogenesis therapies in related diseases, including arthritis, but it has been reported that some synthetic types of antiangiogenic drugs have potential side effects. In recent years, the importance of finding alternative strategies for regulating angiogenesis has begun to attract the attention of researchers. Therefore, identification of natural ingredients used to prevent or treat angiogenesis-related diseases will play a greater role. Isookanin is a phenolic flavonoid presented in Bidens extract, and it has been reported that isookanin possesses some biological properties, including antioxidative and anti-inflammatory effects, anti-diabetic properties, and an ability to inhibit α-amylase. However, its antiangiogenic effects and mechanism thereof have not been studied yet. In this study, our results indicate that isookanin has an effective inhibitory effect on the angiogenic properties of microvascular endothelial cells. Isookanin shows inhibitory effects in multiple stages of PGE2-induced angiogenesis, including the growth, proliferation, migration, and tube formation of microvascular endothelial cells. In addition, isookanin induces cell cycle arrest in S phase, which is also the reason for subsequent inhibition of cell proliferation. The mechanism of inhibiting angiogenesis by isookanin is related to the inhibition of PGE2-mediated ERK1/2 and CREB phosphorylation. These findings make isookanin a potential candidate for the treatment of angiogenesis-related diseases.


Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Chalconas/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dinoprostona/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Modelos Biológicos , Fosforilação
2.
Life Sci ; 279: 119703, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34111458

RESUMO

BACKGROUND: miRNAs are involved in plaque formation of atherosclerosis and vessel restenosis. In this study, we investigated the effects of miR-599, miR-204, and miR-181b on VSMC proliferation, and migration through TGFß receptor 2 (TGFßR2), ß-arrestin 2 (ß-ARR2), SMAD2/p-SMAD2, and ERK1/2/p-ERK1/2. MATERIALS & METHODS: Genes and miRNAs were predicted by bioinformatics tools and were transfected by PEI-miRNAs (miR-599, miR-204, and miR-181b) complexes into VSMCs. The gene and protein expression levels were evaluated by real-time RT-PCR and western blotting techniques, respectively. The VSMC proliferation and migration were studied by MTT and scratch assay, respectively. RESULTS: The miR-181b and miR-204 downregulated significantly ß-ARR2 gene and protein expression levels and p-ERK1/2 values. Moreover, TGFßR2 gene and protein expression levels and p-SMAD2 values were not significantly affected by miR-181b and miR-204. The VSMC proliferation (p = 0.0019, p = 0.0054, respectively) and migration (p < 0.0001, p < 0.0001, respectively) were inhibited by the miR-181b and miR-204. The miR-599 inhibited VSMC proliferation (p = 0.044) and migration (p = 0.0055) but it did not affect significantly the ß-ARR2 and TGFßR2 gene and protein expression levels. CONCLUSION: The results suggested that the inhibitory effects of miR-181b and miR-204 on VSMC proliferation and migration are mediated by the ß-ARR2/p-ERK1/2 pathway. Since VSMC proliferation and migration are involved in plaque growth, therefore this pathway can be a therapeutic target for atherosclerosis.


Assuntos
Movimento Celular , Proliferação de Células , Regulação da Expressão Gênica , MicroRNAs/genética , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Redes Reguladoras de Genes , Humanos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/fisiologia , Transdução de Sinais , beta-Arrestina 2/genética , beta-Arrestina 2/metabolismo
3.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070901

RESUMO

Glycosaminoglycans (GAGs) and proteoglycans (PGs) are major components of the glycocalyx. The secreted GAG and CD44 ligand hyaluronic acid (HA), and the cell surface PG syndecan-1 (Sdc-1) modulate the expression and activity of cytokines, chemokines, growth factors, and adhesion molecules, acting as critical regulators of tumor cell behavior. Here, we studied the effect of Sdc-1 siRNA depletion and HA treatment on hallmark processes of cancer in breast cancer cell lines of different levels of aggressiveness. We analyzed HA synthesis, and parameters relevant to tumor progression, including the stem cell phenotype, Wnt signaling constituents, cell cycle progression and apoptosis, and angiogenic markers in luminal MCF-7 and triple-negative MDA-MB-231 cells. Sdc-1 knockdown enhanced HAS-2 synthesis and HA binding in MCF-7, but not in MDA-MB-231 cells. Sdc-1-depleted MDA-MB-231 cells showed a reduced CD24-/CD44+ population. Furthermore, Sdc-1 depletion was associated with survival signals in both cell lines, affecting cell cycle progression and apoptosis evasion. These changes were linked to the altered expression of KLF4, MSI2, and miR-10b and differential changes in Erk, Akt, and PTEN signaling. We conclude that Sdc-1 knockdown differentially affects HA metabolism in luminal and triple-negative breast cancer model cell lines and impacts the stem phenotype, cell survival, and angiogenic factors.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glicocálix/metabolismo , Ácido Hialurônico/metabolismo , Sindecana-1/genética , Neoplasias de Mama Triplo Negativas/genética , Via de Sinalização Wnt/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Antígeno CD24/genética , Antígeno CD24/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Bases de Dados Factuais , Feminino , Glicocálix/química , Glicocálix/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Hialuronan Sintases/genética , Hialuronan Sintases/metabolismo , Ácido Hialurônico/farmacologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Células MCF-7 , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Análise de Sobrevida , Sindecana-1/antagonistas & inibidores , Sindecana-1/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
4.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073872

RESUMO

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Amidas/farmacologia , Citocinas/metabolismo , Etanolaminas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ácidos Palmíticos/farmacologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Amidas/uso terapêutico , Animais , Etanolaminas/uso terapêutico , Imuno-Histoquímica , Inflamação/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/patologia , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Ácidos Palmíticos/uso terapêutico , Peroxidase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
Nucleic Acids Res ; 49(10): 5867-5880, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34048556

RESUMO

Mammalian oocyte maturation is driven by strictly regulated polyadenylation and translational activation of maternal mRNA stored in the cytoplasm. However, the poly(A) polymerase (PAP) that directly mediates cytoplasmic polyadenylation in mammalian oocytes has not been determined. In this study, we identified PAPα as the elusive enzyme that catalyzes cytoplasmic mRNA polyadenylation implicated in mouse oocyte maturation. PAPα was mainly localized in the germinal vesicle (GV) of fully grown oocytes but was distributed to the ooplasm after GV breakdown. Inhibition of PAPα activity impaired cytoplasmic polyadenylation and translation of maternal transcripts, thus blocking meiotic cell cycle progression. Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPα, 537, 545 and 558, thereby leading to increased activity. This mechanism is responsible for translational activation of transcripts lacking cytoplasmic polyadenylation elements in their 3'-untranslated region (3'-UTR). In turn, activated PAPα stimulated polyadenylation and translation of the mRNA encoding its own (Papola) through a positive feedback circuit. ERK1/2 promoted Papola mRNA translation in a 3'-UTR polyadenylation signal-dependent manner. Through these mechanisms, PAPα activity and levels were significantly amplified, improving the levels of global mRNA polyadenylation and translation, thus, benefiting meiotic cell cycle progression.


Assuntos
Meiose , Oócitos/metabolismo , Oogênese , Polinucleotídeo Adenililtransferase/metabolismo , RNA Mensageiro Estocado/metabolismo , Animais , Ciclo Celular , Citoplasma/metabolismo , Vesículas Citoplasmáticas/metabolismo , Células HeLa , Humanos , Meiose/genética , Camundongos , Camundongos Endogâmicos ICR , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Oogênese/genética , Fosforilação , Poliadenilação , Polinucleotídeo Adenililtransferase/antagonistas & inibidores , Polinucleotídeo Adenililtransferase/genética , Biossíntese de Proteínas , RNA Mensageiro Estocado/genética , RNA Interferente Pequeno , Fuso Acromático/genética , Fuso Acromático/metabolismo , Regulação para Cima
6.
Int J Biol Macromol ; 182: 910-920, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33865893

RESUMO

Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase that plays a crucial role in signal transduction. Previous studies have demonstrated that TRAF6 is overexpressed in hepatocellular carcinoma (HCC) and that TRAF6 knockdown dramatically attenuates tumor cell growth. Thus, TRAF6 may represent a potential therapeutic target for the treatment of HCC. Herein, we identified bis (4-hydroxy-3,5-dimethylphenyl) sulfone (TMBPS) as a novel inhibitor that can directly bind to and downregulate the level of TRAF6. In vitro experimental results showed that TMBPS arrests the cell cycle in the G2/M phase by inactivating the protein kinase B (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways and induces apoptosis by activating the p38/mitogen-activated protein kinase (MAPK) signaling pathway. In addition, TMBPS exhibited significant tumor growth inhibition in mouse xenograft models. In summary, our findings offer a proof-of-concept for the use of TMBPS as a novel chemotherapy drug for the prevention or treatment of HCC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Sulfonas/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sulfonas/química , Sulfonas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
FASEB J ; 35(5): e21598, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33871068

RESUMO

Fibrillin-1 is an extracellular matrix protein which contains one conserved RGD integrin-binding motif. It constitutes the backbone of microfibrils in many tissues, and mutations in fibrillin-1 cause various connective tissue disorders. Although it is well established that fibrillin-1 interacts with several RGD-dependent integrins, very little is known about the associated intracellular signaling pathways. Recent published evidence identified a subset of miRNAs regulated by fibrillin-1 RGD-cell adhesion, with miR-1208 among the most downregulated. The present study shows that the downregulated miR-1208 controls fibroblast proliferation. Inhibitor experiments revealed that fibrillin-1 RGD suppressed miR-1208 expression via c-Src kinase and the downstream JNK signaling. Bioinformatic prediction and experimental target sequence validation demonstrated four miR-1208 binding sites on the ERK2 mRNA and one on the MEK1 mRNA. ERK2 and MEK1 are critical proliferation-promoting kinases. Decreased miR-1208 levels elevated the total and phosphorylated ERK1/2 and MEK1/2 protein levels and the phosphorylated to total ERK1/2 ratio. Together, the data demonstrate a novel outside-in signaling mechanism explaining how fibrillin-1 RGD-cell binding regulates fibroblast proliferation.


Assuntos
Fibrilina-1/metabolismo , Fibroblastos/citologia , MicroRNAs/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Oligopeptídeos/metabolismo , Processamento Pós-Transcricional do RNA , Proliferação de Células , Células Cultivadas , Fibrilina-1/genética , Fibroblastos/metabolismo , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Oligopeptídeos/genética
8.
Toxins (Basel) ; 13(3)2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806711

RESUMO

Zearalenone (ZEN) is a mycotoxin that has been reported to damage various types of cells/tissues, yet its effects on endothelial cells (ECs) have never been investigated. Therefore, this study investigates the potential effects of ZEN using bovine aortic ECs (BAECs). In this study, we found that ZEN induced apoptosis of BAECs through increased cleavage of caspase 3 and poly ADP-ribose polymerase (PARP). ZEN also increased phosphorylation of ERK1/2 and p53, and treatment with the ERK1/2 or p53 inhibitor reversed ZEN-induced EC apoptosis. Transfection of BAECs with small interfering RNA against ERK1/2 or p53 revealed ERK1/2 as an upstream target of p53 in ZEN-stimulated apoptosis. ZEN increased the production of reactive oxygen species (ROS), yet treatment with the antioxidant did not prevent EC apoptosis. Similarly, blocking of estrogen receptors by specific inhibitors also did not prevent ZEN-induced apoptosis. Finally, chelation of cytosolic calcium (Ca2+) using BAPTA-AM or inhibition of endoplasmic reticulum (ER) Ca2+ channel using 2-APB reversed ZEN-induced EC apoptosis, but not by inhibiting ER stress using 4-PBA. Together, our findings demonstrate that ZEN induces EC apoptosis through an ERK1/2/p53/caspase 3 signaling pathway activated by Ca2+ release from the ER, and this pathway is independent of ROS production and estrogen receptor activation.


Assuntos
Apoptose/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Caspase 3/metabolismo , Células Endoteliais/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Zearalenona/toxicidade , Animais , Bovinos , Células Cultivadas , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Fosforilação , Proteína Supressora de Tumor p53/genética
9.
Life Sci ; 276: 119407, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794254

RESUMO

AIMS: The aim of the study was to investigate the interaction between cannabinoid CB1/CB2 and lysophosphatidic acid (LPA) receptors in controlling neuronal signaling and fate. METHODS: HT22 hippocampal cells were treated with different cannabinoid and LPA receptor agonists and antagonists. Western blot and immunofluorescence microscopy were used to study intracellular signaling and the expression of apoptotic markers. Cell viability was determined by a luminescence assay. KEY FINDINGS: Cannabinoid agonists induced activation of both ERK1/2 and p38 MAP kinases. The effects of the CB1/CB2 receptor agonist HU210 were antagonized by the CB1 antagonist rimonabant, whereas the responses to the CB2 agonist JWH133 were blocked by the CB2 antagonist SR144528. HU210 reduced the apoptotic cell death induced by the pro-inflammatory cytokine TNF-α, whereas JWH133 enhanced the cytokine cytotoxicity. Blockade of ERK1/2 and p38 MAPK activation abrogated the HU210 pro-survival and the JWH133 pro-apoptotic effects, respectively. HU210 and the endocannabinoid anandamide, but not JWH133, potentiated ERK1/2 stimulation by LPA and the tricyclic antidepressant amitriptyline acting through the LPA1 receptor. HU210 enhanced amitriptyline-stimulated CREB phosphorylation and protection against TNF-α-induced apoptosis, whereas JWH133 had no effect. ERK1/2 stimulation by either HU210 or amitriptyline was dependent on fibroblast growth factor receptor (FGF-R) kinase activity and the combination of the two stimulants induced FGF-R phosphorylation. Moreover, the CB1 receptor was found to co-immunoprecipitate with the LPA1 receptor. CONCLUSIONS: In HT22 hippocampal cells CB1 and CB2 receptors differentially regulate TNF-α-induced apoptosis and CB1 receptors positively interact with amitriptyline-stimulated LPA1 in promoting FGF-R-mediated ERK1/2 signaling and neuroprotection.


Assuntos
Apoptose , Agonistas de Receptores de Canabinoides/farmacologia , Hipocampo/patologia , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Inibidores da Captação Adrenérgica/farmacologia , Amitriptilina/farmacologia , Animais , Sobrevivência Celular , Células Cultivadas , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Receptores de Ácidos Lisofosfatídicos/genética , Transdução de Sinais
10.
Int J Mol Sci ; 22(8)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918729

RESUMO

Constitutive photomorphogenic 1 (COP1) is the ubiquitin E3 ligase that mediates degradation of c-Jun protein upon Erk1/2 inactivation. It remains unknown how this protein degradation pathway is regulated. In this study, we investigated the roles of protein phosphatases, ubiquitin-conjugating E2 enzymes (UBE2), and an intrinsic motif of c-Jun in regulating this degradation pathway. By using pharmacological inhibitors and/or gene knockdown techniques, we identified protein phosphatase 1 (PP1) and PP2A as the phosphatases and UBE23d as the UBE2 promoting c-Jun degradation, triggered by Erk1/2 inactivation. In addition, we report that the C-terminus of c-Jun protein facilitates its degradation. The addition of a C-terminal tag or deletion of the last four amino acid residues from the C-terminus of c-Jun protects it from degradation under Erk1/2-inactivating conditions. Taken together, this study reveals that the Erk1/2 inactivation-triggered and COP1-mediated c-Jun degradation is extrinsically and intrinsically regulated, providing a new understanding of the mechanisms underlying this protein degradation pathway.


Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Animais , Linhagem Celular Tumoral , Ativação Enzimática , Humanos , Camundongos , Modelos Biológicos , Fosfoproteínas Fosfatases/metabolismo , Ligação Proteica , Proteólise
11.
Biochem Biophys Res Commun ; 553: 58-64, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33756346

RESUMO

Human embryonic stem cells (hESCs) have the unique feature of unlimited self-renewal and differentiation into derivatives of all three germ layers in human body, providing a powerful in vitro model for studying cell differentiation. FGF2, BMP4 and TGF-ß signaling have been shown to play crucial roles in mesendodermal differentiation of hESCs. However, their underlying molecular mechanisms and other signaling pathways potentially involved in mesendodermal differentiation of hESCs remain to be further investigated. In this study, we uncover that VEGF signaling pathway plays a critical role in the mesendodermal induction of hESCs. Treating hESCs with Lenvatinib, a pan-inhibitor of VEGF receptors (VEGFRs), impedes their mesendodermal induction. Conversely, overexpression of VEGFA165, a major human VEGF isoform, promotes the mesendodermal differentiation. Similar to the VEGFR inhibitor, MEK inhibitor PD0325901 hinders mesendodermal induction of hESCs. In contrast, overexpression of ERK2GOF, an intrinsically active ERK2 mutant, markedly reduces the inhibitory effect of the VEGFR inhibitor. Thus, the MEK-ERK cascade plays an important role for the function of VEGF signaling pathway in the mesendodermal induction of hESCs. All together, this study identifies the critical role of VEGF signaling pathway as well as potential crosstalk of VEGF signaling pathway with other known signaling pathways in mesendodermal differentiation of hESCs.


Assuntos
Endoderma/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Embrionárias Humanas/metabolismo , Sistema de Sinalização das MAP Quinases , Mesoderma/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Benzamidas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína Smad1/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteína Smad5/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética
12.
PLoS Biol ; 19(3): e3001063, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33684096

RESUMO

The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell-targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2-/- CD4+ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines. Spry2 deficiency abrogated type 2 inflammation and airway hyperreactivity in a murine model of asthma. Spry2 expression was higher in blood and airway CD4+ T cells from patients with asthma, and Spry2 knockdown impaired human T cell proliferation and cytokine production. Spry2 deficiency up-regulated the lipid raft protein caveolin-1, enhanced its interaction with CSK, and increased CSK interaction with LCK, culminating in augmented inhibitory phosphorylation of LCK. Knockdown of CSK or dislodgment of caveolin-1-bound CSK restored ERK1/2 activation in Spry2-/- T cells, suggesting an essential role for Spry2 in LCK activation and T cell function.


Assuntos
Asma/fisiopatologia , Proteína Tirosina Quinase CSK/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Proteínas de Membrana/metabolismo , Adulto , Animais , Asma/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Ativação Linfocitária , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/fisiologia
13.
Arch Biochem Biophys ; 703: 108846, 2021 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-33744198

RESUMO

CCAAT/enhancer-binding protein ß (C/EBPß) is a transcription factor that is involved in adipocytic and monocytic differentiation. However, the physiological role of C/EBPß in megakaryocytes (MKs) is not clear. In this study, we investigated the effects of C/EBPß on the early-stage differentiation of MKs, and explored the potential mechanisms of action. We established a cytosine arabinoside-induced thrombocytopenia mouse model using C57BL/6 mice. In the thrombocytopenia mice, the platelet count was found to be decreased, and the mRNA and protein expression levels of C/EBPß in MKs were also reduced. Furthermore, the maturation of Dami (MKs cell line) cells was induced by phorbol 12-myristate 13-acetate. When C/EBPß was silenced in Dami cells by transfection using C/EBPß-small interfering RNA, the expression of MKs-specific markers CD41 and CD62P, was dramatically decreased, resulting in morphological changes and differentiation retardation in low ploidy, which were evaluated using flow cytometry, real-time polymerase chain reaction, western blot, and confocal microscopy. The mitogen activated protein kinase-extracellular signal-regulated kinase signaling pathway was found to be required for the differentiation of MKs; knockdown of C/EBPß in MEK/ERK1/2 pathway attenuated MKs differentiation. Overexpression of C/EBPß in MEK/ERK1/2 pathway inhibited by U0126 did not promote MKs differentiation. To the best of our knowledge, C/EBPß plays an important role in MKs differentiation and polyploidy cell cycle control. Taken together, C/EBPß may have thrombopoietic effects in the differentiation of MKs, and may assist in the development of treatments for various disorders.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Diferenciação Celular , Megacariócitos/citologia , Trombopoese , Animais , Proteína beta Intensificadora de Ligação a CCAAT/deficiência , Proteína beta Intensificadora de Ligação a CCAAT/genética , Linhagem Celular , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fatores de Tempo
14.
Biochem Biophys Res Commun ; 554: 63-70, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33780861

RESUMO

Pancreatic cancer is a digestive tract malignancy characterized by an occult onset and rapid progression. The genetic heterogeneity of pancreatic cancer is closely related to its highly malignant biological behavior. The myelin and lymphocyte protein 2 (MAL2) is upregulated in multiple cancers at the transcriptional level. However, the exact role of MAL2 in pancreatic cancer remains elusive. In this study, we demonstrated that MAL2 protein and mRNA levels were upregulated in pancreatic cancer. MAL2 overexpression was significantly associated with poor prognosis in patients with pancreatic cancer. We further showed that MAL2 interacted with IQGAP1 to increase ERK1/2 phosphorylation levels, which promoted pancreatic cancer progression. Therefore, these results suggest that MAL2 could be a novel therapeutic target for pancreatic cancer.


Assuntos
Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Biologia Computacional , Bases de Dados Genéticas , Humanos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosforilação , Prognóstico , Domínios e Motivos de Interação entre Proteínas , Taxa de Sobrevida , Proteínas Ativadoras de ras GTPase/genética
15.
Environ Toxicol Pharmacol ; 84: 103626, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33621689

RESUMO

Arsenic is a metalloid that has been hypothesized to be an environmental risk factor for Alzheimer's disease (AD), a disease having hyperphosphorylated tau aggregate as a marker. The present study demonstrated that prolonged exposure to sodium arsenite at low micromolar range (1-10 µM) reduced Tau 1 (recognizing dephosphorylated tau at residues 189-207) and elevated pS202 tau in differentiated human neuroblastoma SH-SY5Y cells indicating that arsenic increases tau phosphorylation in neurons. Sodium arsenite elevated GSK3ß kinase activity, while GSK3 inhibitors, BIO, SB216763, and lithium, reversed the Tau 1 reduction by sodium arsenite. Additionally, sodium arsenite increased levels of active phosphorylation of ERK1/2, and inhibition of ERK1/2 by U0126 partially improved the Tau1 reduction. These results suggest that arsenic may cause tau hyperphosphorylation in neurons through the activation of GSK3 and ERK1/2. Furthermore, sodium arsenite augmented tau phosphorylation in the membrane and cytosolic fractions. Inductions of GSK3 activity by sodium arsenite treatment were observed in the membrane fraction, as evidenced by a reduction of ß-catenin, a protein signaled for degradation following phosphorylation by GSK3. An enhancement of ERK1/2 phosphorylation by sodium arsenite was also witnessed in the cytosol. Additionally, sodium arsenite increased insoluble tau aggregation. These results suggest that arsenic induces tau hyperphosphorylation in the membrane fraction which may lead to its redistribution from the membrane fraction to the cytosol, where it promotes neurofibrillary formation. Collectively, we demonstrate that prolonged arsenic exposure increases tau phosphorylation, partly through GSK3 and ERK1/2 activation, and insoluble tau aggregates, hence possibly contributing to the development of sporadic AD.


Assuntos
Arsênio/toxicidade , Poluentes Ambientais/toxicidade , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas tau/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Citosol/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos
16.
J Biol Chem ; 296: 100449, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33617879

RESUMO

Hck, a Src family nonreceptor tyrosine kinase (SFK), has recently been established as an attractive pharmacological target to improve pulmonary function in COVID-19 patients. Hck inhibitors are also well known for their regulatory role in various malignancies and autoimmune diseases. Curcumin has been previously identified as an excellent DYRK-2 inhibitor, but curcumin's fate is tainted by its instability in the cellular environment. Besides, small molecules targeting the inactive states of a kinase are desirable to reduce promiscuity. Here, we show that functionalization of the 4-arylidene position of the fluorescent curcumin scaffold with an aryl nitrogen mustard provides a stable Hck inhibitor (Kd = 50 ± 10 nM). The mustard curcumin derivative preferentially interacts with the inactive conformation of Hck, similar to type-II kinase inhibitors that are less promiscuous. Moreover, the lead compound showed no inhibitory effect on three other kinases (DYRK2, Src, and Abl). We demonstrate that the cytotoxicity may be mediated via inhibition of the SFK signaling pathway in triple-negative breast cancer and murine macrophage cells. Our data suggest that curcumin is a modifiable fluorescent scaffold to develop selective kinase inhibitors by remodeling its target affinity and cellular stability.


Assuntos
Curcumina/farmacologia , Desenho de Fármacos , Células Epiteliais/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-hck/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Clonagem Molecular , Curcumina/análogos & derivados , Curcumina/síntese química , Estabilidade de Medicamentos , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Células HEK293 , Células HT29 , Humanos , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-hck/química , Proteínas Proto-Oncogênicas c-hck/genética , Proteínas Proto-Oncogênicas c-hck/metabolismo , Células RAW 264.7 , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Quinases da Família src/genética , Quinases da Família src/metabolismo
17.
Neuroscience ; 463: 227-237, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33540053

RESUMO

Activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling in cardiovascular regulatory regions of the brain contributes to sympathetic excitation in myocardial infarction (MI)-induced heart failure (HF) by increasing brain renin-angiotensin system (RAS) activity, neuroinflammation, and endoplasmic reticulum (ER) stress. The mechanisms eliciting brain ERK1/2 signaling in HF are still poorly understood. We tested the involvement of the epidermal growth factor receptor (EGFR) which, upon activation, stimulates ERK1/2 activity. Adult male Sprague-Dawley rats received bilateral microinjections of a lentiviral vector encoding a small interfering RNA (siRNA) for EGFR, or a scrambled siRNA, into the hypothalamic paraventricular nucleus (PVN), a recognized source of sympathetic overactivity in HF. One week later, coronary artery ligation was performed to induce HF. Four weeks later, the EGFR siRNA-treated HF rats, compared with the scrambled siRNA-treated HF rats, had lower mRNA and protein levels of EGFR, lower levels of phosphorylated (p-) EGFR and p-ERK1/2 and lower mRNA levels of the inflammatory mediators TNF-α, IL-1ß and cyclooxygenase-2, the RAS components angiotensin-converting enzyme and angiotensin II type 1a receptor and the ER stress markers BIP and ATF4 in the PVN. They also had lower plasma and urinary norepinephrine levels and improved peripheral manifestations of HF. Additional studies revealed that p-EGFR was increased in the PVN of HF rats, compared with sham-operated control rats. These results suggest that activation of EGFR in the PVN triggers ERK1/2 signaling, along with ER stress, neuroinflammation and RAS activity, in MI-induced HF. Brain EGFR may be a novel target for therapeutic intervention in MI-induced HF.


Assuntos
Receptores ErbB/genética , Insuficiência Cardíaca , Núcleo Hipotalâmico Paraventricular , Animais , Inativação Gênica , Masculino , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Sprague-Dawley , Sistema Nervoso Simpático/metabolismo
18.
Chem Pharm Bull (Tokyo) ; 69(2): 178-184, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33518600

RESUMO

C1q/tumor necrosis factor (TNF)-related protein 12 (CTRP12) plays a crucial part in cardiovascular diseases especially the coronary artery disease. Nonetheless, it is unrevealed that whether the CTRP12 participates in the progress of cardiac fibrosis. In this study, we investigated whether CTRP12 regulates pathological myocardial fibrosis. We isolated neonatal rat cardiac fibroblasts were cultured with recombination CTRP12 followed by stimulating with Isoproterenol (ISO, 100 µM) for 24 h. Then the adenovirus were used to achieve the CTRP12-overexpressed fibroblasts. In vivo, the C57/B6 mice were subjected to recombinant human CTRP12 (0.2 µg/g/d) for 2 weeks after injected with Isoproterenol (ISO, 10 mg/kg/d for 3 d then 5 mg/kg/d for 11 d, subcutaneously (s.c.), 2 weeks) and mice were also subjected to adenovirus with P38 overexpressing system to explore the mechanism. As a result, CTRP12 significantly inhibit the transformation of cardiac fibroblasts to myofibroblasts and the transcription of cardiac fibrosis-related proteins induced by ISO in vitro. The administration of CTRP12 can effectively reduce the cardiac fibrosis and enhance the cardiac function in mice hearts. The treatment with CTRP12 did not change the expression level of phosphorylated (p)-smad2, smad4, p-extracellular regulated protein kinases 1/2 and c-Jun N-terminal kinase 1/2, but it suppressed the activation of p38. Cardiac overexpression of p38 could abolish this kind of cardioprotective effects by CTRP12. In summary, the CTRP12 protect against the ISO induced cardiac fibrosis via suppressing the p38 signal pathway.


Assuntos
Adipocinas/farmacologia , Isoproterenol/toxicidade , Transdução de Sinais/efeitos dos fármacos , Adipocinas/genética , Adipocinas/metabolismo , Animais , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibrose , Cardiopatias/etiologia , Cardiopatias/prevenção & controle , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Proteína Smad2/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Eur Rev Med Pharmacol Sci ; 25(1): 145-153, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33506902

RESUMO

OBJECTIVE: The incidence of pulmonary adenocarcinoma locates first in all the malignant tumors in the world. At present, there are many diagnostic methods for pulmonary adenocarcinoma, but there are a few methods that are mature or have ideal application prospects. We aim to explore the role of VRK2 in the occurrence and development of pulmonary adenocarcinoma and its possible regulatory mechanism. PATIENTS AND METHODS: Western blot and qRT-PCR were performed to assess the expression of VRK2. Flow cytometry, Western blot, and Caspase-3 colorimetric assay Kit were used to evaluate the apoptosis level. The proliferation, migration, and invasion ability were measured via cell cycle assay, wound healing, and transwell invasion assay. Luciferase assay verified the relationship between VRK2 and miR-145-5p. The effect of FGD5-AS1 on tumorigenesis of glioma was detected by the xenograft nude mice model. RESULTS: VRK2 was significantly increased in tumor tissues and cell lines. Loss of VRK2 promoted apoptosis level and inhibited the proliferation, migration, and invasion in A549 cells via regulating the ERK1/2/AKT signal pathway. Luciferase assay reported that VRK2 could bind with miR-145-5p. The level of miR-145-5p was negatively correlated with the expression of VRK2 and involved in VRK2 regulating tumor progression. The tumor growth assay showed that the silencing of VRK2 inhibited tumorigenesis with the inactivating ERK1/2/AKT pathway. CONCLUSIONS: Knockdown of VRK2 inhibited the development of pulmonary adenocarcinoma via regulating the ERK1/2/AKT signal pathway by targeting miR-145-5p, which providing some novel experimental basis for clinical treatment of pulmonary adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Adenocarcinoma de Pulmão/patologia , Animais , Apoptose , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , MicroRNAs/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Tumorais Cultivadas
20.
Life Sci ; 267: 118978, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33412209

RESUMO

AIMS: Vascular smooth muscle cell (VSMC) phenotype shift is involved in the pathophysiology of vascular injury or platelet-derived growth factor (PDGF)-induced abnormal proliferation and migration of VSMCs. We aimed to investigate the underlying mechanism involved in PDGF-mediated signaling pathways and autophagy regulation followed by VSMC phenotype shift. MAIN METHODS: The proliferation, migration and apoptosis of cultured rat aortic VSMCs were measured, and cells undergoing phenotype shift and autophagy were examined. Specific inhibitors for target proteins in signaling pathways were applied to clarify their roles in regulating cell functions. KEY FINDINGS: PDGF-BB stimulation initiated autophagy activation and synthetic phenotype transition by decreasing α-smooth muscle-actin (SMA), calponin and myosin heavy chain (MHC) and increasing osteopontin (OPN) expression. However, U0126, a potent extracellular signal-regulated kinase 1/2 (Erk1/2) inhibitor, decreased PDGF-BB-induced LC3 expression, while rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), increased it. Furthermore, U0126 decreased the expresseion of autophagy-related genes (Atgs) such as beclin-1, Atg7, Atg5, and Atg12-Atg5 complex, indicating that Erk1/2 is a regulator of PDGF-BB-induced VSMC autophagy. Regardless of autophagy inhibition by U0126 or activation by rapamycin, the PDGF-BB-induced decrease in SMA, calponin and MHC and increase in OPN expression were inhibited. Furthermore, PDGF-BB-stimulated VSMC proliferation, migration and proliferating cell nuclear antigen (PCNA) expression were inhibited by U0126 and rapamycin. SIGNIFICANCE: These findings suggest that PDGF-BB-induced autophagy is strongly regulated by Erk1/2, an mTOR-independent pathway, and any approach for targeting autophagy modulation is a potential therapeutic strategy for addressing abnormal VSMC proliferation and migration.


Assuntos
Autofagia/fisiologia , Becaplermina/metabolismo , Músculo Liso Vascular/metabolismo , Animais , Becaplermina/genética , Becaplermina/farmacologia , Proteínas de Ligação ao Cálcio , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas dos Microfilamentos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miócitos de Músculo Liso/metabolismo , Miosinas , Fenótipo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
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