K. Virdee et Am. Tolkovsky, ACTIVATION OF P44 AND P42 MAP KINASES IS NOT ESSENTIAL FOR THE SURVIVAL OF RAT SYMPATHETIC NEURONS, European journal of neuroscience, 7(10), 1995, pp. 2159-2169
We have examined whether activation of MAP kinases [or extracellular s
ignal-regulated kinases (ERKs)] is required for the survival of rat sy
mpathetic neurons by comparing the actions of three survival factors w
hose survival-promoting actions can be blocked by neutralizing Fab fra
gments to p21ras (Nobes and Tolkovsky, 1995, Eur. J. Neurosci., 7, 344
-350), nerve growth factor (NGF), the cytokines ciliary neurotrophic f
actor (CNTF) and leukaemia inhibitory factor (LIF), and the cyclic AMP
analogue 4-(8-chlorophenylthio)cAMP (CPTcAMP). NGF-induced survival w
as accompanied by an intense (15- to 30-fold) and steady (>24 h) activ
ation of p44 and p42 ERKs which waned rapidly (t(1/2) similar to 30 mi
n) upon NGF withdrawal. However, concentrations of NGF that induced a
weak (4- to 5-fold) stimulation of the ERKs were not sufficient to mai
ntain long-term survival. Moreover, prolonged and intense stimulation
of the ERKs by NGF for up to 15.5 h was unable to confer long-term sur
vival, since withdrawal of NGF after this time resulted in neuronal de
ath that was kinetically indistinguishable from the death of neurons t
hat had not been exposed to NGF. By contrast, CNTF and LIF continued t
o support survival for up to 3 days after eliciting only transient (<3
0 min and 1 h respectively) activation of p44 and p42 ERKs, while CPTc
AMP induced survival for several days without any measurable activatio
n of the ERKs, Taken together, these data suggest that ERK activation
per se is neither necessary nor sufficient for survival and that alter
native pathways exist for effecting long-term survival of rat sympathe
tic neurons.