Akt-1 mediates survival of chondrocytes from endoplasmic reticulum-induced stress.
J Cell Physiol
; 222(3): 502-8, 2010 Mar.
Article
em En
| MEDLINE
| ID: mdl-20020442
ABSTRACT
The unfolded protein response (UPR) is an evolutionary conserved adaptive mechanism that permits cells to react and adjust to conditions of endoplasmic reticulum (ER) stress. In addition to UPR, phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal regulated kinase (ERK) signaling pathways protect a variety of cells from ER stress. The goal of the present study was to assess the susceptibility of chondrocytes to ER stress and to determine the signaling pathways involved in their survival. We found that low concentration of thapsigargin (10 nM) reduced the viability of a chondrocyte cell line (N1511 cells) and that these cells were approximately 100 fold more susceptible to thapsigargin-induced stress than fibroblasts. Interestingly, in thapsigargin and tunicamycin-stressed chondrocytes induction of the proapoptotic transcription factor CHOP preceded that of the anti-apoptotic BiP by 12 h. Although both of these agents caused sustained Akt and ERK phosphorylation; inhibition of Akt phosphorylation sensitized chondrocytes to ER stress, while blocking ERK signaling by U0126 had no effect. We found that Akt-1, but not Akt-2 or Akt-3, is predominantly expressed in N1511 chondrocytes. Furthermore, siRNA-mediated knockdown of Akt-1 sensitized chondrocytes to ER stress, which was associated with increased capsase-3 activity and decreased Bcl(XL) expression. These data suggest that under condition of ER stress, multiple signaling processes regulate chondrocyte's survival-death decisions. Thus, rapid upregulation of CHOP likely contributes to chondrocyte death, while Akt-1-mediated inactivation of caspase 3 and induction of BclXL promotes survival.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Estresse Fisiológico
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Transdução de Sinais
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Condrócitos
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Retículo Endoplasmático
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Proteínas Proto-Oncogênicas c-akt
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article