Fibroblast growth factor 2 applied to the optic nerve after axotomy increases Bcl-2 and decreases Bax in ganglion cells by activating the extracellular signal-regulated kinase signaling pathway.
We have shown that application of basic fibroblast growth factor (FGF-2) to axotomized optic nerve promotes the survival of frog retinal ganglion cells (RGCs). In the present study we used western blotting and immunocytochemistry to investigate the effects of this FGF-2 treatment upon the activation of the extracellular signal-regulated kinase (ERK) pathway, the amounts and distribution of Bcl-2 family proteins, and the activation of caspase-3. Axotomy alone temporarily increased ERK activation; FGF-2 treatment to the nerve prolonged this activation. This effect was blocked by U0126, a selective ERK kinase (MEK) inhibitor. Axotomy caused a decrease in Bcl-2 and a small increase in Bcl-x(L). FGF-2 treatment caused an ERK-dependent increase in Bcl-2 and an ERK-independent increase in Bcl-x(L). The pro-apoptotic Bax was increased by axotomy; FGF-2 treatment greatly decreased Bax levels, an effect that was inhibited by U0126. Axotomy induced the cleavage of caspase-3; FGF-2 treatment blocked this effect in an ERK-dependent manner. Finally, intraocular application of the MEK inhibitor caused a large reduction in the survival-promoting effect that FGF-2 application to the nerve stump had on RGCs. Our results suggest that FGF-2 acts, at least in part, via the ERK pathway to prevent apoptosis of axotomized RGCs not only by increasing amounts of anti-apoptotic proteins, but also by a striking reduction in the levels of apoptotic effectors themselves.
Ríos-Muñoz
Wilson
W
Institute of Neurobiology, Department of Anatomy, University of Puerto Rico Medical Sciences Campus, Old San Juan, Puerto Rico.
Soto
Ileana
I
Duprey-Díaz
Mildred V
MV
Blagburn
Jonathan
J
Blanco
Rosa E
RE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D019771:Axotomy; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000201:enzymology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism*; D011894:Rana pipiens; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D016222:Fibroblast Growth Factor 2; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D053148:Caspase 3; D020169:Caspases