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1.
Nat Commun ; 4: 2354, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23965929

RESUMO

Mitsugumin 53 (MG53) negatively regulates skeletal myogenesis by targeting insulin receptor substrate 1 (IRS-1). Here, we show that MG53 is an ubiquitin E3 ligase that induces IRS-1 ubiquitination with the help of an E2-conjugating enzyme, UBE2H. Molecular manipulations that disrupt the E3-ligase function of MG53 abolish IRS-1 ubiquitination and enhance skeletal myogenesis. Skeletal muscles derived from the MG53-/- mice show an elevated IRS-1 level with enhanced insulin signalling, which protects the MG53-/- mice from developing insulin resistance when challenged with a high-fat/high-sucrose diet. Muscle samples derived from human diabetic patients and mice with insulin resistance show normal expression of MG53, indicating that altered MG53 expression does not serve as a causative factor for the development of metabolic disorders. Thus, therapeutic interventions that target the interaction between MG53 and IRS-1 may be a novel approach for the treatment of metabolic diseases that are associated with insulin resistance.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Insulina/metabolismo , Desenvolvimento Muscular/genética , Músculo Esquelético/metabolismo , Animais , Proteínas de Transporte/genética , Diferenciação Celular , Linhagem Celular , Diabetes Mellitus/metabolismo , Dieta Hiperlipídica , Teste de Tolerância a Glucose , Proteínas Substratos do Receptor de Insulina/genética , Resistência à Insulina , Masculino , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitinação
2.
Exp Cell Res ; 319(10): 1451-62, 2013 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-23567182

RESUMO

The AKT and ERK signaling pathways are known to be involved in cell hypertrophy, proliferation, survival and differentiation. Although there is evidence for crosstalk between these two signaling pathways in cellulo, there is less evidence for cross talk in vivo. Here, we show that crosstalk between AKT and ERK signaling in the hearts of TRIM72-overexpressing transgenic mice (TRIM72-Tg) with alpha-MHC promoter regulates and maintains their heart size. TRIM72, a heart- and skeletal muscle-specific protein, downregulates AKT-mTOR signaling via IRS-1 degradation and reduces the size of rat cardiomyocytes and the size of postnatal TRIM72-Tg hearts. TRIM72 expression was upregulated by hypertrophic inducers in cardiomyocytes, while IRS-1 was downregulated by IGF-1. TRIM72 specifically regulated IGF-1-dependent AKT-mTOR signaling, resulting in a reduction of the size of cardiomyocytes. Postnatal TRIM72-Tg hearts were smaller than control-treated hearts with inhibition of AKT-mTOR signaling. However, adult TRIM72-Tg hearts were larger than of control despite the suppression of AKT-mTOR signaling. Activation of ERK, PKC-α, and JNK were observed to be elevated in adult TRIM72-Tg, and these signals were mediated by ET-1 via the ET receptors A and B. Altogether, these results suggest that AKT signaling regulates cardiac hypertrophy in physiological conditions, and ERK signaling compensates for the absence of AKT signaling during TRIM72 overexpression, leading to pathological hypertrophy.


Assuntos
Proteínas de Transporte/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Coração/fisiopatologia , Sistema de Sinalização das MAP Quinases , Miócitos Cardíacos/metabolismo , Animais , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Proteínas de Transporte/genética , Feminino , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Coração/efeitos dos fármacos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Masculino , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Tamanho do Órgão , Fosforilação , Gravidez , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Serina-Treonina Quinases TOR/metabolismo
3.
Proteomics ; 10(13): 2498-515, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20422640

RESUMO

Since detergent-resistant lipid rafts play important roles in the signal transduction for myogenesis, their comprehensive proteomic analysis could provide new insights to understand their function in myotubes. Here, the detergent-resistant lipid rafts were isolated from C2C12 myotubes and analyzed by capillary RPLC/MS/MS. Among the 327 proteins (or protein groups) identified, 28% were categorized to the plasma membrane or raft proteins, 29% to mitochondria, 20% to microsomal proteins, 10% to other proteins, and 13% to unknown proteins. The localization of oxidative phosphorylation (OXPHOS) complexes in the sarcolemma lipid rafts was further confirmed from C2C12 myotubes by cellular fractionation, surface-biotin labeling, immunofluorescence, and lipid raft fractionation. After adding exogenous cytochrome c, the sarcolemma isolated from myotubes had an ability to consume oxygen in the presence of NADH or succinate. The generation of NADH-dependent extracellular superoxide was increased by inhibiting or downregulating OXPHOS I, III, and IV in myotubes, indicating that OXPHOS proteins are major sources for extracellular ROS in skeletal muscle. With all these data, we can conclude that OXPHOS proteins are associated with the sarcolemma lipid rafts during C2C12 myogenesis to generate extracellular ROS.


Assuntos
Detergentes/farmacologia , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Mitocôndrias/metabolismo , Desenvolvimento Muscular , Oxigênio/metabolismo , Animais , Linhagem Celular , Camundongos , Fosforilação , Proteômica
4.
Cancer Lett ; 287(2): 196-206, 2010 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-19616371

RESUMO

Hepatocellular carcinoma (HCC) frequently includes abnormalities in cell cycle regulators, including up-regulated cyclin-dependent kinase (Cdks) activities due to loss or low expression of Cdk inhibitors. In this study, we show that xylocydine, a cyclin-dependent kinase (Cdk) specific inhibitor, is a good anti-cancer drug candidate for HCC treatment. Xylocydine (50muM) selectively down-regulates the activity of Cdk1 and Cdk2, accompanied by significant cell growth inhibition in HCC cells. Xylocydine also strongly inhibits the activity of Cdk7 and Cdk9, in vitro as well as in cell cultures, that is temporally associated with apoptotic cell death in xylocydine-induced HCC cells. This is associated with inhibition of phosphorylation of RNA polymerase II at serine residues 5 and 2, which are targets of Cdk7 and Cdk9, respectively. The effects on apoptosis are concomitant with changes in the levels of anti-apoptotic proteins, Bcl-2, XIAP, and survivin, which are markedly down-regulated, and pro-apoptotic molecules, p53 and Bax, which are elevated in HCC cells after treatment with xylocydine. The up-regulated level of p53 was associated with increased stability of the protein, as levels of Ser15 and Ser392 phsophorylated p53 are similarly elevated in the inhibitor treated cells. We demonstrated that xylocydine can effectively suppress the growth of HCC xenografts in Balb/C-nude mice by preferentially inducing apoptosis in the xenografts, whereas the drug did not cause any apparent toxic effect on other tissues. Taken together, these data suggest that the novel Cdk inhibitor xylocydine is a good candidate for an anti-cancer drug for HCC therapy.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Nucleosídeos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Proteína Quinase CDC2/antagonistas & inibidores , Proteína Quinase CDC2/metabolismo , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Polimerase II/metabolismo , Fatores de Tempo , Carga Tumoral , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/metabolismo , Quinase Ativadora de Quinase Dependente de Ciclina
5.
Biochem Biophys Res Commun ; 385(2): 154-9, 2009 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-19445898

RESUMO

Lipid rafts are plasma membrane platforms mediating signal transduction pathways for cellular proliferation, differentiation and apoptosis. Here, we show that membrane fluidity was increased in HeLa cells following treatment with ginsenoside Rh2 (Rh2), as determined by cell staining with carboxy-laurdan (C-laurdan), a two-photon dye designed for measuring membrane hydrophobicity. In the presence of Rh2, caveolin-1 appeared in non-raft fractions after sucrose gradient ultracentrifugation. In addition, caveolin-1 and GM1, lipid raft landmarkers, were internalized within cells after exposure to Rh2, indicating that Rh2 might disrupt lipid rafts. Since cholesterol overloading, which fortifies lipid rafts, prevented an increase in Rh2-induced membrane fluidity, caveolin-1 internalization and apoptosis, lipid rafts appear to be essential for Rh2-induced apoptosis. Moreover, Rh2-induced Fas oligomerization was abolished following cholesterol overloading, and Rh2-induced apoptosis was inhibited following treatment with siRNA for Fas. This result suggests that Rh2 is a novel lipid raft disruptor leading to Fas oligomerization and apoptosis.


Assuntos
Antineoplásicos/farmacologia , Apoptose , Ginsenosídeos/farmacologia , Microdomínios da Membrana/efeitos dos fármacos , Receptor fas/metabolismo , Caveolina 1/metabolismo , Colesterol/metabolismo , Células HeLa , Humanos , Ligantes , Microdomínios da Membrana/metabolismo
6.
Mol Cells ; 28(6): 509-13, 2009 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-20552320

RESUMO

Here, we show that JNK1 and JNK3 have different roles in TNF-alpha- or etoposide-induced apoptosis in HeLa cells. Dominant negative JNK1 inhibited TNF-alpha- or etoposide-induced apoptosis, while dominant negative JNK3 promoted TNF-alpha- or etoposide-induced apoptosis. During TNF-alpha-induced apoptosis, JNK1 was activated in a biphasic manner, exhibiting both transient and sustained activity, whereas JNK3 was activated early and in a transient manner. The role of JNK3 activation was an anti-apoptotic effect, while the role of JNK1 activation was a pro-apoptotic effect. These results suggest that the anti-apoptotic mechanism of JNK3 in TNF-alpha-induced apoptosis originates before the apoptotic machinery is triggered.


Assuntos
Apoptose/efeitos dos fármacos , Etoposídeo/farmacologia , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/farmacologia , Morte Celular , Células HeLa , Humanos
7.
Biochem Biophys Res Commun ; 361(4): 994-9, 2007 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-17686459

RESUMO

Here we demonstrate that JNK3 can phosphorylate Smac. Smac phosphorylation attenuates its ability to activate apoptosome activity in HeLa S-100 cell lysates. Addition of the X-linked inhibitor of apoptosis protein (XIAP) to the S-100 markedly suppresses apoptosome activity, and this suppressive effect of XIAP is neutralized by adding unphosphorylated Smac, but not phosphorylated Smac. Furtherover, JNK3-mediated phosphorylation of Smac markedly attenuates the interaction between Smac and XIAP, as measured by BIACORE assays and non-denaturing gel shift assays. When JNK3 activity is down-regulated in etoposide-induced HeLa cells by transiently overexpressing a dominant negative version of JNK3 (DN-JNK3), the caspase-3 activity as well as PARP cleavages are markedly enhanced. And the interaction of Smac with XIAP also increases by down-regulating JNK3 activity under the same conditions. These results suggest that JNK3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between Smac and XIAP.


Assuntos
Apoptose , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Mitocondriais/metabolismo , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Proteínas Reguladoras de Apoptose , Etoposídeo/farmacologia , Células HeLa , Humanos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Fosforilação
8.
J Pharmacol Exp Ther ; 319(3): 1276-85, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16973888

RESUMO

We show here that Ca(2+) and reactive oxygen species (ROS) are involved in the up-regulation of c-Jun NH(2)-terminal kinase 1 (JNK1) activity during apoptosis induced by ginsenoside Rh2 (G-Rh2) in HeLa, MCF10A-ras, and MCF7 cells. Addition of antioxidants such as N-acetyl-l-cysteine or catalase attenuates G-Rh2-induced ROS generation, JNK1 activation, and apoptosis. The overexpression of catalase down-regulates caspase-3 and JNK1 activities. G-Rh2 treatment of cells results in mitochondrial depolarization, second mitochondrial activator of caspase release, and translocation of Bax into the mitochondria, and these events are inhibited by antioxidants. Ca(2+) is also involved in mitochondrial depolarization during G-Rh2-induced apoptosis. These results suggest that ROS and Ca(2+) are important signaling intermediates leading to stress-activated protein kinase/extracellular signal-regulated kinase kinase 1/JNK1 activation and depolarization of the mitochondrial membrane potential in G-Rh2-induced apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Ginsenosídeos/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/metabolismo , Proteínas Reguladoras de Apoptose , Western Blotting , Cálcio/fisiologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Citometria de Fluxo , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Microscopia Confocal , Proteínas Mitocondriais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/enzimologia , Translocação Genética/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
9.
J Cell Biol ; 174(1): 77-88, 2006 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-16801388

RESUMO

We show that caspase-3 cleaves Cdc6 at D(290)/S and D(442)/G sites, producing p32-tCdc6 (truncated Cdc6) and p49-tCdc6, respectively, during etoposide- or tumor necrosis factor (TNF)-alpha-induced apoptosis. The expression of these tCdc6 proteins, p32- and p49-tCdc6, promotes etoposide-induced apoptosis. The expression of tCdc6 perturbs the loading of Mcm2 but not Orc2 onto chromatin and activates ataxia telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR) kinase activities with kinetics similar to that of the phosphorylation of Chk1/2. The activation kinetics are consistent with elevated cellular levels of p53 and mitochondrial levels of Bax. The tCdc6-induced effects are all suppressed to control levels by expressing a Cdc6 mutant that cannot be cleaved by caspase-3 (Cdc6-UM). Cdc6-UM expression attenuates the TNF-alpha-induced activation of ATM and caspase-3 activities. When ATM or ATR is down-expressed by using the small interfering RNA technique, the TNF-alpha- or tCdc6-induced activation of caspase-3 activities is suppressed in the cells. These results suggest that tCdc6 proteins act as dominant-negative inhibitors of replication initiation and that they disrupt chromatin structure and/or induce DNA damage, leading to the activation of ATM/ATR kinase activation and p53-Bax-mediated apoptosis.


Assuntos
Apoptose/fisiologia , Caspases/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Apoptose/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia , Caspase 3 , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/genética , Células Cultivadas , Dano ao DNA , Proteínas de Ligação a DNA/genética , Etoposídeo/farmacologia , Células HeLa , Humanos , Modelos Biológicos , Dados de Sequência Molecular , Proteínas Nucleares/biossíntese , Proteínas Serina-Treonina Quinases/genética , Fator de Necrose Tumoral alfa/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/genética , Proteína X Associada a bcl-2/metabolismo
10.
J Pharmacol Exp Ther ; 308(3): 814-9, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14617691

RESUMO

Xylocydine (4-amino-6-bromo-7-(beta-l-xylofuranosyl)pyrrolo[2,3-d]pyrimidine-5-carboxamide) blocks cyclin-dependent kinase CDK1 and CDK2/cyclin A activity in vitro (IC(50) 1.4 and 61 nM, respectively) while minimally inhibiting the three other Ser/Thr protein kinases tested (IC(50) 21-86 microM). Reduced phosphorylated nucleolin and retinoblastoma protein levels showed it also efficiently inhibited cellular CDK1 and CDK2 activity (IC(50) 50-100 and 200-500 nM, respectively). Moreover, it blocked the functional activity of CDKs in tumor necrosis factor-related apoptosis-inducing ligand-induced SK-HEP-1 cell apoptosis 20 to 1000-fold more potently than olomoucine and roscovitine. Xylocydine is thus a novel and potent CDK inhibitor that could be used to interfere with cell cycle- and apoptosis-related CDK activity in various diseases.


Assuntos
Apoptose , Quinases Ciclina-Dependentes/antagonistas & inibidores , Citidina/análogos & derivados , Citidina/farmacologia , Inibidores Enzimáticos/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Reguladoras de Apoptose , Proteína Quinase CDC2/antagonistas & inibidores , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Linhagem Celular , Quinase 2 Dependente de Ciclina , Interações Medicamentosas , Humanos , Ligantes , Glicoproteínas de Membrana/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF , Células Tumorais Cultivadas
11.
J Biol Chem ; 278(50): 50330-7, 2003 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-14514687

RESUMO

We show here that JNK1 activity is rapidly up-regulated and prolonged by specific mechanisms during apoptosis induced by paclitaxel- or ginsenoside-Rh2 in SK-HEP-1 cells. The early phase of JNK1 activation is prevented in cells expressing the dominant negative SEK1 mutant, although this JNK1 perturbation does not prevent apoptotic cell death. The later phase of JNK1 activation, which is temporally coincided with caspase-dependent cleavage of JNK1-associated p21(WAF1/CIP1), is efficiently prevented by expressing p21D112N, an uncleavable mutant of p21(WAF1/CIP1) and this perturbation of JNK1 activation results in prevention of apoptosis. The later JNK1 activation and apoptotic progression are also prevented by co-treatments of cells with rottlerin, a PKC-delta inhibitor or z-VAD-fmk, a pan caspase inhibitor. We also provide evidence that apoptotic cell death is significantly promoted in cells expressing JNK1, while this apoptotic cell death is effectively suppressed in cells expressing the dominant negative JNK1 mutant (DN-JNK1) or JBD, a JNK inhibitor protein. Thus, the later phase of JNK1 activation, which is linked to a caspase-dependent mechanism that requires PKC-delta activity, is associated with the induction of apoptosis, while the early JNK1 activation that is associated with a SEK1-mediated mechanism is not directly involved in apoptotic progression.


Assuntos
Regulação Enzimológica da Expressão Gênica , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Acetofenonas/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Benzopiranos/farmacologia , Western Blotting , Caspase 3 , Inibidores de Caspase , Caspases/metabolismo , Morte Celular , Linhagem Celular , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Genes Dominantes , Ginsenosídeos/farmacologia , Humanos , Imuno-Histoquímica , Proteínas Quinases JNK Ativadas por Mitógeno , Microscopia de Fluorescência , Proteínas Quinases Ativadas por Mitógeno/genética , Paclitaxel/farmacologia , Testes de Precipitina , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C-delta , Fatores de Tempo , Transfecção , Regulação para Cima
12.
Biochem Biophys Res Commun ; 304(2): 358-64, 2003 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-12711323

RESUMO

We provide here evidence that c-Jun N-terminal protein kinase 1 (JNK1) activity is differentially up-regulated during apoptosis of SK-HEP-1 cells after treatment with ginsenoside Rh2 (G-Rh2). The G-Rh2-mediated JNK1 activation that occurred for the first 10-30min was associated with SEK1 activity, but thereafter, the sustained activation was associated not with SEK1 activity, but with proteolytic cleavage of JNK1-associated p21(WAF1/CIP1). Supporting this is that the expression of the dominant negative SEK1 mutant effectively blocked the early JNK1 activation phase but did not alter the sustained activation phase or apoptosis. Furthermore, expression of p21D112N, an uncleavable mutant of p21(WAF1/CIP1), suppressed the later JNK1 activation. Moreover, the stable overexpression of ectopic JNK1 suppressed apoptosis while expression of the dominant negative JNK1 mutant promoted it. We propose that the early SEK1-associated JNK1 activation phase acts to prolong cell survival in response to apoptosis-inducing agents, thereby serving as an intervening checkpoint prior to the commitment to apoptosis.


Assuntos
Apoptose , Ginsenosídeos/farmacologia , MAP Quinase Quinase 4 , Quinases de Proteína Quinase Ativadas por Mitógeno/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Sobrevivência Celular , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/metabolismo , Ativação Enzimática , Humanos , Cinética , Sistema de Sinalização das MAP Quinases , Proteína Quinase 8 Ativada por Mitógeno , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Mutação , Células Tumorais Cultivadas
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