The transcription factor E2F1 promotes dopamine‐evoked neuronal apoptosis by a mechanism independent of transcriptional activation

The E2F1 transcription factor plays an important role in promoting neuronal apoptosis; however, it is not clear how E2F1 does this. Here we show that E2F1 is involved in dopamine (DA)‐evoked apoptosis in cerebellar granule neurons (CGNs). E2F1 –/– CGNs and CGNs expressing an antisense E2F1 cDNA were significantly protected from DA‐toxicity relative to controls. The neuronal protection was accompanied by significantly reduced caspase 3 activity. E2F1‐mediated neuronal apoptosis did not require activation of gene transcription because: (1) ectopic expression of E2F1 or its mutants lacking the transactivation domain induced neuronal apoptosis, whereas an E2F1 mutant lacking the DNA‐binding domain did not; (2) under all of these conditions, known E2F1 target genes including cyclin A, cdc2 and p19ARF were not induced; and (3) DA‐evoked neuronal apoptosis was associated with up‐regulated E2F1, but not transcription of its target genes. Finally, E2F1‐mediated neuronal apoptosis was associated with reduced nuclear factor (NF)‐κB DNA‐binding activity. Taken together, these data suggest that E2F1 promotes DA‐evoked caspase 3‐dependent neuronal apoptosis by a mechanism independent of gene transactivation, and this may possibly occur through inhibition of anti‐apoptotic genes including NF‐κB.