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Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path?
A Copani1, D Uberti, M A Sortino
1Dept of Pharmaceutical Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy.
Abstract:
Cell-cycle-related proteins, such as cyclins or cyclin-dependent kinases, are re-expressed in neurons committed to death in response to a variety of insults, including excitotoxins, hypoxia and ischemia, loss of trophic support, or beta-amyloid peptide. In some of these conditions events that are typical of the mid-G1 phase, such as cyclin-dependent kinase 4/6 activation, are required for the induction of neuronal death. In other cases, the cycle must proceed further and recruit steps that are typical of the G1/S transition for death to occur. Finally, there are conditions in which cell-cycle proteins might be re-expressed, but do not contribute to neuronal death. We hypothesize that cell-cycle signaling becomes a mandatory component of neuronal 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 threshold, a cell-cycle signaling becomes crucial for the induction of neuronal death through p53-dependent or -independent pathways.
Insights
Cell-cycle proteins re-emerge in dying neurons, especially when DNA damage is low. This cell-cycle re-entry becomes essential for neuronal death induction via p53-dependent or -independent pathways.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Cell-cycle proteins like cyclins and cyclin-dependent kinases are re-expressed in neurons undergoing death due to various insults.
- Neuronal death can involve different cell-cycle phases, from mid-G1 to the G1/S transition, or may not involve cell-cycle proteins at all.
Purpose of the Study:
- To investigate the role of cell-cycle re-entry in neuronal death under conditions of varying DNA damage.
- To elucidate the hypothesis that cell-cycle signaling becomes critical for neuronal demise when other death mechanisms are insufficient.
Main Methods:
- The study reviews existing literature on cell-cycle protein re-expression in neurons following insults like excitotoxicity, hypoxia, ischemia, and beta-amyloid exposure.
- Analysis of conditions where cell-cycle events (e.g., CDK4/6 activation, G1/S transition) are implicated in neuronal death induction.
Main Results:
- Cell-cycle protein re-expression is observed in neurons facing diverse insults.
- Neuronal death induction can be dependent on specific cell-cycle phases (mid-G1 or G1/S transition).
- Cell-cycle signaling is hypothesized to be mandatory for neuronal death when DNA damage is below a critical threshold.
Conclusions:
- Cell-cycle re-entry is crucial for neuronal death when DNA damage is insufficient to trigger other death pathways.
- The extent of DNA damage dictates whether cell-cycle signaling becomes a mandatory component of neuronal demise.
- This process can occur through p53-dependent or p53-independent mechanisms.