R. M. Ramalho and P. S. Ribeiro contributed equally to this work.
Inhibition of the E2F-1/p53/Bax pathway by tauroursodeoxycholic acid in amyloid β-peptide-induced apoptosis of PC12 Cells
Article first published online: 16 JUN 2004
Journal of Neurochemistry
Volume 90, Issue 3, pages 567–575, August 2004
How to Cite
Ramalho, R. M., Ribeiro, P. S., Solá, S., Castro, R. E., Steer, C. J. and Rodrigues, C. M. P. (2004), Inhibition of the E2F-1/p53/Bax pathway by tauroursodeoxycholic acid in amyloid β-peptide-induced apoptosis of PC12 Cells. Journal of Neurochemistry, 90: 567–575. doi: 10.1111/j.1471-4159.2004.02517.x
- Issue published online: 18 JUN 2004
- Article first published online: 16 JUN 2004
- Received February 11, 2004; revised manuscript received March 18, 2004; accepted March 19, 2004.
- Bcl-2 proteins;
- bile acids;
- retinoblastoma protein
Amyloid β-peptide (Aβ)-induced cell death may involve activation of the E2F-1 transcription factor and other cell cycle-related proteins. In previous studies, we have shown that tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, modulates Aβ-induced apoptosis by interfering with crucial events of the mitochondrial pathway. In this study, we examined the role of E2F and p53 activation in the induction of apoptosis by Aβ, and investigated novel molecular targets for TUDCA. The results showed that despite Bcl-2 up-regulation, PC12 neuronal cells underwent significant apoptosis after incubation with the active fragment Aβ (25–35), as assessed by DNA fragmentation, nuclear morphology and caspase-3-like activation. In addition, transcription through the E2F-1 promoter was significantly induced and associated with loss of the retinoblastoma protein. In contrast, levels of E2F-1, p53 and Bax proteins were markedly increased. Overexpression of E2F-1 in PC12 cells was sufficient to induce p53 and Bax proteins, as well as nuclear fragmentation. Notably, TUDCA modulated Aβ-induced apoptosis, E2F-1 induction, p53 stabilization and Bax expression. Further, TUDCA protected PC12 cells against p53- and Bax-dependent apoptosis induced by E2F-1 and p53 overexpression, respectively. In conclusion, the results demonstrate that Aβ-induced apoptosis of PC12 cells proceeds through an E2F-1/p53/Bax pathway, which, in turn, can be specifically inhibited by TUDCA, thus underscoring its potential therapeutic use.