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-bcl-2 cell line up-regulates ha-ras 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.

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