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1.
Biochem Biophys Res Commun ; 627: 97-102, 2022 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-36030658

RESUMO

A nuclear serine/threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) is a critical regulator of development and DNA damage response. HIPK2 can induce apoptosis under cellular stress conditions and thus its protein level is maintained low by constant proteasomal degradation. In the present study, we present evidence that TNF receptor-associated factor 2 (TRAF2) regulates the protein stability of HIPK2. Overexpression of TRAF2 decreased while its knockdown increased the HIPK2 protein level. The TRAF2-mediated decrease in HIPK2 protein expression was blocked by proteasomal inhibitor. In addition, TRAF2 decreased the protein half-life of HIPK2. We found that HIPK2 and TRAF2 co-immunoprecipitated. Interestingly, the co-immunoprecipitation was reduced while HIPK2 protein level increased following TNFα treatment, suggesting TNFα induced dissociation of TRAF2 from HIPK2 to accumulate HIPK2. Inhibition of HIPK2 partially suppressed TNFα-induced cell death, indicating that the accumulated HIPK2 may contribute to the TNFα-induced cell death. Our results suggest that TRAF2 can regulate proapoptotic function of HIPK2 by promoting proteasomal degradation.


Assuntos
Proteínas Serina-Treonina Quinases , Fator de Necrose Tumoral alfa , Apoptose , Proteínas Serina-Treonina Quinases/genética , Estabilidade Proteica , Fator 2 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Ubiquitina-Proteína Ligases/metabolismo
2.
Int J Neurosci ; 123(1): 42-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22937735

RESUMO

Plasminogen activator inhibitor-1 (PAI-1) is a soluble factor that is released from astrocytes, the most abundant type of glial cell in the brain. PAI-1 was initially identified as inhibiting two types of plasminogen activators, that is, tissue-type plasminogen and urokinase activators that are known to lead to the proteolytic degradation of the extracellular matrix. Recently, PAI-1 was reported to mediate the neuroprotective activity of transforming growth factor-ß1 against N-methyl-D-aspartate receptor-mediated excitotoxicity and to be involved in angiogenesis following ischemic stroke, independently of the effects via the inhibition of tissue-type plasminogen and urokinase-type plasminogen activators. In this study, we examined whether PAI-1 influences synaptogenesis and neurotoxicity induced by amyloid beta peptide(1-42) (Aß(1-42)) in rat primary hippocampal neurons. Using immunostaining, treatment with PAI-1 for 24 h was found to significantly upregulate synaptophysin, postsynaptic density-95, and the polysialylated form of neural cell adhesion molecule, compared to treatment with vehicle alone. In addition, PAI-1 has neuroprotective effects against Aß(1-42)-induced cytotoxicity in rat primary cultured hippocampal neurons. Taken together, our results suggest that PAI-1 has therapeutic potential in Alzheimer's disease by promoting synaptogenesis and by demonstrating neuroprotective effects against Aß(1-42)-oligomer-induced neurotoxicity in rat primary cultured hippocampal neurons.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Hipocampo/citologia , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Inibidor 1 de Ativador de Plasminogênio/farmacologia , Sinapses/efeitos dos fármacos , Análise de Variância , Animais , Células Cultivadas , Proteína 4 Homóloga a Disks-Large , Feto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , L-Lactato Desidrogenase , Proteínas de Membrana/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neurônios/enzimologia , Ratos , Ácidos Siálicos/metabolismo , Sinaptofisina/metabolismo , Regulação para Cima/efeitos dos fármacos
3.
J Pharmacol Sci ; 119(1): 73-81, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22739235

RESUMO

Neuregulin-1 (NRG1) plays important roles in the development and plasticity of the brain, and it is also reported to have potent neuroprotective properties. We previously reported that NRG1 has neuroprotective actions against Swedish amyloid precursor protein-induced neurotoxicity. In addition to the amyloid beta peptide, other metabolites of amyloid precursor protein (APP) such as the C-terminal fragments of APP (APP-CTs) have been reported to possess cytotoxic effects in neuronal cells. In this study, we investigated whether NRG1 exerts neuroprotective effects against APP-CTs and attempted to determine its neuroprotective mechanisms. NRG1 attenuated the neurotoxicities induced by the expression of APP-CTs in neuronal cells. NRG1 also reduced the accumulation of reactive oxygen species and attenuated mitochondrial membrane potential loss induced by APP-CTs. In addition, NRG1 upregulated the expression of the anti-apoptotic protein Bcl-2. This effect was blocked by the inhibition of ErbB4, a key NRG1 receptor. Taken together, these results demonstrate the neuroprotective potential of NRG1 in Alzheimer's disease.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Receptores ErbB/metabolismo , Neuregulina-1/metabolismo , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Encéfalo/metabolismo , Morte Celular/fisiologia , Humanos , Potencial da Membrana Mitocondrial/fisiologia , Neurônios/metabolismo , Síndromes Neurotóxicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor ErbB-4 , Superóxido Dismutase/metabolismo , Regulação para Cima
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