A Specific Pathway to Neuronal Death

Science's STKE  25 Mar 2003:
Vol. 2003, Issue 175, pp. tw119-TW119
DOI: 10.1126/stke.2003.175.tw119

Konishi and Bonni determined that activity-deprivation--but not growth factor withdrawal--stimulated Cdc2 (cyclin-dependent kinase 2) expression and Cdc2-dependent neuronal apoptosis. Apoptosis is crucial to normal brain development and contributes to several neurodegenerative diseases. Although cell-cycle proteins have been implicated in apoptosis in postmitotic neurons, neither the mechanisms whereby these proteins are reactivated, nor the mechanisms through which they elicit apoptosis are clearly understood. Konishi and Bonni used Western analysis on cultured rat cerebellar granule cells--in which apoptosis is suppressed by neuronal activity (mimicked by depolarizing conditions) or exposure to growth factors--to show that withdrawal from depolarizing conditions stimulated Cdc2 expression and phosphorylation of the target protein BAD (Bcl-2-associated death promoter). Activity deprivation and growth factor withdrawal both lead to caspase-3 cleavage; the latter, however, did not stimulate Cdc2 expression or BAD phosphorylation. Moreover, the Cdc2 inhibitor roscovitine suppressed apoptosis in response to activity deprivation, but not growth factor withdrawal. Mutational analysis of a cdc2-reporter gene implicated an E2F-binding element in activity-deprivation apoptosis, and electrophoretic mobility-shift assays implicated the E2F1 transcription factor. E2F1 overexpression stimulated cdc2 promoter-dependent transcription and expression of endogenous Cdc2 and also elicited apoptosis. Chromatin immunoprecipitation analysis, as well as expression of an E2F1 dominant negative, substantiated the role of this pathway in activity-dependent apotosis. Activity deprivation did not, however, stimulate DNA synthesis (seen in mitotic cells following activation of the E2F-Cdc2 pathway). These data thus define a novel Cdc2-dependent pathway for activity-dependent apoptosis and draw a distinction between the mechanisms underlying activity-dependent and growth factor-dependent apoptosis.

Y. Konishi, A. Bonni, The E2F-Cdc2 cell-cycle pathway specifically mediates activity deprivation-induced apoptosis of postmitotic neurons. J. Neurosci. 23 1649-1658 (2003). [Abstract] [Full Text]