Corticotropin-releasing factor (CRF) rapidly suppresses apoptosis by acting upstream of the activation of caspases
Version of Record online: 18 FEB 2003
Journal of Neurochemistry
Volume 84, Issue 5, pages 1074–1085, March 2003
How to Cite
Radulovic, M., Hippel, C. and Spiess, J. (2003), Corticotropin-releasing factor (CRF) rapidly suppresses apoptosis by acting upstream of the activation of caspases. Journal of Neurochemistry, 84: 1074–1085. doi: 10.1046/j.1471-4159.2003.01594.x
- Issue online: 18 FEB 2003
- Version of Record online: 18 FEB 2003
- Received July 4, 2002; revised manuscript received October 31, 2002; accepted November 15, 2002.
- corticotropin-releasing factor
The physiological role of the corticotropin-releasing factor (CRF) family of peptides has recently been extended by emerging evidence of their cytoprotective effects. To determine whether CRF-mediated cytoprotection is linked to caspase-dependent apoptosis, the effect of CRF on the activation of caspases was investigated in detail in Y79 human retinoblastoma cells. The results presented here demonstrate that the cytoprotective effect of CRF against the actions of camptothecin (CT) was mediated by CRF receptor subtype 1, but not subtype 2. The observed CRF-mediated cytoprotection involved rapid and pronounced suppression of proteolytic processing and activation of procaspase-3, exerted even when CRF was added hours after the application of the cytotoxic agent. Surprisingly, activation of procaspase-3 preceded activation of the initiator procaspases 2, 8, 9 and 10 during CT-induced apoptosis of Y79 cells. The mechanism of the effect of CRF was examined using inhibitors of signalling pathways such as Wortmannin (Akt), cyclic AMP-dependent protein kinase (PKA), extracellular signal-regulated kinase (ERK), protein kinase c (PKC), p38 mitogen-activated protein kinase (p38 MAPK), phospholipase c (PLC), nuclear factor-κB (NF-κΒ) and c-jun N-terminal kinase (JNK). The involvement of PKA in the mediation of the anti-apoptotic effect of CRF has been established. Taken together, these results demonstrate for the first time that the cytoprotective effect of CRF involved suppression of pro-apoptotic pathways at a site upstream of activation of procaspase-3.