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The flow of new information on gene expression related to apoptosis has been relentless in the last several years. This has also been the case with respect to gene expression after cerebral ischemia. Many of genes associated with an apoptotic mode of cell death have now been studied in the context of experimental cerebral ischemia from the immediate early genes through modulating genes such as bcl-2 to genes in the final execution phase such as interleukin-1β converting enzyme (ICE)-related proteases. It was impossible to adequately cite all primary reports on these subjects. However, many excellent reviews have appeared in the last year, which together, cover all these areas of interest. In this review, we have elected to cite only reports published since January 1996 and use an extensive collection of reviews (indicated in italics) to guide the reader to the earlier literature. Our intent is to provide the reader with a timely and useful analysis of the current state of the art. It is hoped that this approach does not cause offense with our colleagues whose contributions before 1996 laid the foundation for much of this work.

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Abstract:The transcription factor E2F1 is known to mediate apoptosis in isolated quiescent and postmitotic cardiac myocytes, and its absence decreases the size of brain infarction following cerebral ischemia. To demonstrate directly that E2F1 modulates neuronal apoptosis, we used cultured cortical neurons to show a temporal association of the transcription and expression of E2F1 in neurons with increased neuronal apoptosis. Cortical neurons lacking E2F1 expression (derived from E2F1 Ϫ/Ϫ mice) were resistant to staurosporine-induced apoptosis as evidenced by the significantly lower caspase 3-like activity and a lesser number of cells with apoptotic morphology in comparison with cortical cultures derived from wild-type mice. Furthermore, overexpressing E2F1 alone using replication-deficient recombinant adenovirus was sufficient to cause neuronal cell death by apoptosis, as evidenced by the appearance of hallmarks of apoptosis, such as the threefold increase in caspase 3-like activity and increased laddered DNA fragmentation, in situ endlabeled DNA fragmentation, and numbers of neuronal cells with punctate nuclei. Taken together, we conclude that E2F1 plays a key role in modulating neuronal apoptosis. Key Words: Cortical neurons-Apoptosis-E2F1-Caspase -DNA fragmentation-Replication-deficient adenovirus. J. Neurochem. 75, 91-100 (2000).Neuronal apoptosis has been implicated in the pathogenesis of several neurodegenerative disorders, such as that occurring during delayed neuronal cell death after ischemia, Huntington's disease, Parkinson's disease, and Alzheimer's disease (Thompson, 1995;Rudin and Thompson, 1997). Although the exact molecular pathways underlying neuronal apoptosis after ischemia or other insults are complex and not fully understood (MacManus and Linnik, 1997;D'Mello, 1998;Lee et al., 1999), we hypothesized that several known cell death elements may play critical roles. One of these elements is the transcription factor E2F1.E2F1, a member of a family of six related growth regulatory transcription factors, was first recognized to promote G1 to S-phase transition by trans-activation of genes involved in DNA synthesis, e.g., dihydrofolate reductase and DNA polymerase ␣, and cell cycle control, e.g., cyclin E and cyclin A (reviewed by Dyson, 1998;Nevins, 1998). In cycling cells, the activity of E2F1 is regulated by the retinoblastoma gene product pRb. Hypophosphorylated pRb forms a complex with E2F1 and represses transcription, perhaps by inhibition of histone deacetylase activities (Brehm et al., 1998;Luo et al., 1998;Magnaghi-Jaulin et al., 1998). During G1/S transition, pRb becomes highly phosphorylated by cell cycledependent kinases, such as Cdk4/6 (Taya, 1997), and releases E2F1. An inappropriate increase in content of free E2F1 has been described as a key regulator of cell death by apoptosis in cycling cells, quiescent cells (Johnson et al., 1993;Qin et al., 1994;Kowalik et al., 1995;DeGregori et al., 1997), and postmitotic myocardium and cardiac myocytes (Kirshenbaum et al., 1996;Agah et al., 1997)...