Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cell Oncol (Dordr) ; 47(3): 1065-1070, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38150153

RESUMO

STAT3 is a pleiotropic transcription factor overactivated in 70% of solid tumours. We have recently reported that inactivating mutations on residues susceptible to post-translational modifications (PTMs) in only one of the monomers (i.e. asymmetric) caused changes in the cellular distribution of STAT3 homodimers. Here, we used more controlled experimental conditions, i.e. without the interference of endogenous STAT3 (STAT3-/- HeLa cells) and in the presence of a defined cytokine stimulus (Leukemia Inhibitory Factor, LIF), to provide further evidence that asymmetric PTMs affect the nuclear translocation of STAT3 homodimers. Time-lapse microscopy for 20 min after LIF stimulation showed that S727 dephosphorylation (S727A) and K685 inactivation (K685R) slightly enhanced the nuclear translocation of STAT3 homodimers, while K49 inactivation (K49R) delayed STAT3 nuclear translocation. Our findings suggest that asymmetrically modified STAT3 homodimers could be a new level of STAT3 regulation and, therefore, a potential target for cancer therapy.


Assuntos
Núcleo Celular , Fator Inibidor de Leucemia , Multimerização Proteica , Processamento de Proteína Pós-Traducional , Fator de Transcrição STAT3 , Fator de Transcrição STAT3/metabolismo , Humanos , Fator Inibidor de Leucemia/metabolismo , Células HeLa , Núcleo Celular/metabolismo , Fosforilação , Transporte Ativo do Núcleo Celular , Transporte Proteico/efeitos dos fármacos
2.
Cells ; 11(2)2022 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-35053415

RESUMO

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective forms of the 520 kDa multidomain protein, sacsin. Sacsin function is exclusively studied on neuronal cells, where it regulates mitochondrial network organization and facilitates the normal polymerization of neuronal intermediate filaments (i.e., neurofilaments and vimentin). Here, we show that sacsin is also highly expressed in astrocytes, C6 rat glioma cells and N9 mouse microglia. Sacsin knockout in C6 cells (C6Sacs-/-) induced the accumulation of the glial intermediate filaments glial fibrillary acidic protein (GFAP), nestin and vimentin in the juxtanuclear area, and a concomitant depletion of mitochondria. C6Sacs-/- cells showed impaired responses to oxidative challenges (Rotenone) and inflammatory stimuli (Interleukin-6). GFAP aggregation is also associated with other neurodegenerative conditions diagnosed in infants, such as Alexander disease or Giant Axonal Neuropathy. Our results, and the similarities between these disorders, reinforce the possible connection between ARSACS and intermediate filament-associated diseases and point to a potential role of glia in ARSACS pathology.


Assuntos
Deleção de Genes , Filamentos Intermediários/metabolismo , Chaperonas Moleculares/metabolismo , Neuroglia/metabolismo , Animais , Animais Recém-Nascidos , Linhagem Celular Tumoral , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Estresse Oxidativo , Ratos Sprague-Dawley , Rotenona/toxicidade
3.
FASEB Bioadv ; 2(2): 116-125, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32123861

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is a ubiquitous and pleiotropic transcription factor that plays essential roles in normal development, immunity, response to tissue damage and cancer. We have developed a Venus-STAT3 bimolecular fluorescence complementation assay that allows the visualization and study of STAT3 dimerization and protein-protein interactions in living cells. Inactivating mutations on residues susceptible to post-translational modifications (PTMs) (K49R, K140R, K685R, Y705F and S727A) changed significantly the intracellular distribution of unstimulated STAT3 dimers when the dimers were formed by STAT3 molecules that carried different mutations (ie they were "asymmetric"). Some of these asymmetric dimers changed the proliferation rate of HeLa cells. Our results indicate that asymmetric PTMs on STAT3 dimers could constitute a new level of regulation of STAT3 signaling. We put forward these observations as a working hypothesis, since confirming the existence of asymmetric STAT3 homodimers in nature is extremely difficult, and our own experimental setup has technical limitations that we discuss. However, if our hypothesis is confirmed, its conceptual implications go far beyond STAT3, and could advance our understanding and control of signaling pathways.

4.
Mol Cell Endocrinol ; 434: 238-49, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27402602

RESUMO

Melatonin (N-acetyl-5-methoxytryptamine) is a highly pleiotropic hormone with antioxidant, antiproliferative, oncolytic and neuroprotective properties. Here, we present evidence that the N-acetyl side chain plays a key role in melatonin's antiproliferative effect in HT22 and sw-1353 cells, but it does so at the expense of antioxidant and neuroprotective properties. Removal of the N-acetyl group enhances the antioxidant and neuroprotective properties of the indole, but it can lead to toxic methamphetamine-like effects in several cell lines. Inhibition of NFkB mimicked melatonin's antiproliferative and antioxidant effects, but not neuroprotection. Our results strongly suggest that neuroprotective and antiproliferative effects of melatonin rely on different parts of the molecule and are likely mediated by different mechanisms. We also predict that melatonin metabolism by target cells could determine whether melatonin inhibits cell proliferation, prevents toxicity or induces cell death (e.g. apoptosis or autophagy). These observations could have important implications for the rational use of melatonin in personalized medicine.


Assuntos
Antioxidantes/farmacologia , Ácido Glutâmico/toxicidade , Hipocampo/efeitos dos fármacos , Melatonina/farmacologia , Fármacos Neuroprotetores/farmacologia , 5-Metoxitriptamina , Animais , Autofagia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Hipocampo/citologia , Humanos , Camundongos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...