Bcl-2 up-regulates ha-ras mRNA expression and induces c-Jun phosphorylation at Ser73 via an ERK-dependent pathway in PC 12 cells.
Members of the Bcl-2 family of proteins function either to promote or to repress apoptosis. Bcl-2 has been mainly localised to the mitochondria and acts predominantly upstream of cytochrome c release in its prevention of apoptosis. Little is known about the function of Bcl-2 independent of an apoptotic stimulus. Here we demonstrate that inducible overexpression of the anti-apoptotic protein Bcl-2 in a PC12 Tet-on- cell line up-regulates mRNA expression and leads to phosphorylation of c-Jun at Ser73 via the ERK pathway in a time and concentration dependent manner. Phosphorylation of c-Jun was inhibited by the addition of the selective ERK inhibitor PD 98059. No activation of the stress-activated protein kinases JNK and p38 could be detected. This is the first evidence of a direct activation of the Ras-Raf-MAPK cascade by an anti-apoptotic protein. We propose that the selective activation of Ras, the ERK pathway and the subsequent phosphorylation of c-Jun contribute to the anti-apoptotic action of Bcl-2.
Schwarz
Cordelia S
CS
Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany.
Seyfried
Jan
J
Evert
Bernd O
BO
Klockgether
Thomas
T
Wüllner
Ullrich
U
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D018628:Gene Dosage; D015870:Gene Expression / Q000502:physiology; D011905:Genes, ras / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D012694:Serine / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D004791:Enzyme Inhibitors; D005419:Flavonoids; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D012694:Serine; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one