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

Abstract

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 signi®cantly protected from DA-toxicity relative to controls. The neuronal protection was accompanied by signi®cantly 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 p19 ARF 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)-kB 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-kB.

Cell cycle molecules and vertebrate neuron death: E2F at the hub

“…When tested in several different systems of cultured neurons, the mutant construct promoted death, indicating a derepression mechanism. 94,104 Additional experimental observations further support a mechanism of neuron death driven at least in part by derepression of E2F-regulated genes. A 'decoy' DNA construct consisting of multiple copies of the E2F-binding site also effectively promoted death of neurons.…”

“…84,104,[106][107][108][109] Overexpression of E2F1 also accelerated loss of T-antigenexpressing Purkinje cells in transgenic mice. 81 Although such findings can and have been viewed as supporting an E2F-dependent gene activation model of neuron death, there are alternative interpretations.…”

“…E2F1 is upregulated in neurons subjected to apoptotic stimuli in vitro 46,68,104,105,107,109 and in vivo 37 and is elevated in degenerating neurons of patients with Alzheimer disease and with Down's syndrome. 93,110 In addition, neurons treated with an E2F1 antisense 68,104 as well as neurons cultured from mice null for E2F1 107,109,[111][112][113] are at least partially protected from diverse apoptotic stimuli. Although such data can be taken to support a mechanism of E2F1-dependent gene activation, here again an alternative interpretation is possible.…”

Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium-induced apoptosis in neurons

“…However, neurons are terminally differentiated and postmitotic, having exited the cell cycle irreversibly. Thus, an increase in the expression of cell cycle proteins may cause unfavorable effects on neurons, specifically inducing the expression of the proapoptotic transcriptional factor E2F-1 (Hou et al, 2001;R.A. Smith et al, 2003).…”

Neuropilin-1 Is a Direct Target of the Transcription Factor E2F1 during Cerebral Ischemia-Induced Neuronal Death In Vivo

“…Previous studies, including our own, have shown that the transcription factor E2F1 plays an important role in modulating ischemiainduced neuronal death (11,19,22,24,44). Adenovirus (Ad)-mediated overexpression of E2F1 in cerebellar granule neurons (CGNs) resulted in neuronal apoptosis (18,20,35), while E2F1-deficient neurons were resistant to death evoked by K ϩ withdrawal (14,44), staurosporine (18), dopamine (19,20), 6-hydroxydopamine (19), and oxygen-glucose deprivation (11). In addition, E2F1 knockout mice were more resistant to ischemia-induced brain damage than their wild-type littermates (32,33).…”