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1.
Cell Death Differ ; 14(12): 2047-57, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17823617

RESUMO

MDMX has been shown to modulate p53 in dividing cells after DNA damage. In this study, we investigated the role of MDMX in primary cultures of neurons undergoing cell death. We found that DNA damage, but also membrane-initiated apoptotic stresses (glutamate receptor; Amyloid beta precursor) or survival factor deprivation downregulated MDMX protein levels. Forced downregulation of murine double minute X (MDMX) by shRNA induced apoptosis suggesting that MDMX is required for survival in neurons. Protease inhibitors prevented the loss of MDMX after neurotoxic treatments, indicating a regulation of protein stability. Some, but not all, neurotoxic stresses induced phosphorylation of MDMX at serine 367, further supporting regulation at the protein level. Interestingly, we found that depending on the stimulus either p53 or E2F1 was induced, but overexpression of MDMX inhibited the transcriptional activity of both proapoptotic factors, and maintained neuronal viability upon neurotoxic stresses. Taken together, our data show that MDMX is an antiapoptotic factor in neurons, whose degradation is induced by various stresses and allows activation of p53 and E2F-1 during neuronal apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Precursor de Proteína beta-Amiloide/toxicidade , Animais , Inibidores de Caspase , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Fator de Transcrição E2F1/metabolismo , Inibidores Enzimáticos/farmacologia , Inativação Gênica/efeitos dos fármacos , Camundongos , Inibidores de Proteassoma , RNA Interferente Pequeno , Proteína Supressora de Tumor p53/metabolismo
2.
Cell Death Differ ; 14(10): 1802-12, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17599098

RESUMO

Sprouty (Spry) proteins are ligand-inducible inhibitors of receptor tyrosine kinases-dependent signaling pathways, which control various biological processes, including proliferation, differentiation and survival. Here, we investigated the regulation and the role of Spry2 in cells of the central nervous system (CNS). In primary cultures of immature neurons, the neurotrophic factor BDNF (brain-derived neurotrophic factor) regulates spry2 expression. We identified the transcription factors CREB and SP1 as important regulators of the BDNF activation of the spry2 promoter. In immature neurons, we show that overexpression of wild-type Spry2 blocks neurite formation and neurofilament light chain expression, whereas inhibition of Spry2 by a dominant-negative mutant or small interfering RNA favors sprouting of multiple neurites. In mature neurons that exhibit an extensive neurite network, spry2 expression is sustained by BDNF and is downregulated during neuronal apoptosis. Interestingly, in these differentiated neurons, overexpression of Spry2 induces neuronal cell death, whereas its inhibition favors neuronal survival. Together, our results imply that Spry2 is involved in the development of the CNS by inhibiting both neuronal differentiation and survival through a negative-feedback loop that downregulates neurotrophic factors-driven signaling pathways.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/fisiologia , Diferenciação Celular/fisiologia , Proteínas de Membrana/metabolismo , Neurônios/citologia , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal , Animais , Apoptose , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Proliferação de Células , Sobrevivência Celular/fisiologia , Células Cultivadas , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/genética , Camundongos , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo
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