Activation of cell cycle-associated proteins in neuronal death: a mandatory or dispensable path?

Cell-cycle-related proteins, such as cyclins or cyclin-dependent kinases, a re reexpressed in neurons committed to death in response to a variety of in sults, including excitotoxins, hypoxia and ischemia, loss of trophic suppor t, or beta -amyloid peptide. In some of these conditions events that are ty pical of the mid-G1 phase, such as cyclin-dependent kin ase 4/6 activation, are required for the induction of neuronal death, In other cases, the cycl e must proceed further and recruit steps that are typical of the G1/S trans ition for death to occur. Finally, there are conditions in which cell-cycle proteins might be re-expressed, but do not contribute to neuronal death. W e hypothesize that cell-cycle signaling becomes a mandatory component of ne uronal demise when other mechanisms are not enough for neurons to reach the threshold for death. Under this scheme, the death threshold is set by the extent of DNA damage, Whenever the extent of DNA damage is below this thres hold, a cell-cycle signaling becomes crucial for the induction of neuronal death through p53-dependent or -independent pathways.