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First published online 1 March 2005
doi: 10.1242/jcs.01724

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p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death

Malika Hamdane¹, Alexis Bretteville^1,*, Anne-Véronique Sambo^1,*, Katharina Schindowski², Séverine Bégard¹, André Delacourte¹, Philippe Bertrand² and Luc Buée^1,

¹ INSERM U422, Institut de Médecine Prédictive et Recherche Thérapeutique, Université de Lille 2, Place de Verdun, 59045 Lille Cedex, France
² Aventis Pharma, CNS Research, 94400 Vitry Sur Seine, France

Author for correspondence (e-mail: buee{at}lille.inserm.fr)

Accepted 13 January 2005

In large models of neuronal cell death, there is a tight correlation between Cdk5 deregulation and cell-cycle dysfunction. However, pathways that link Cdk5 to the cell cycle during neuronal death are still unclear. We have investigated the molecular events that precede p25/Cdk5-triggered neuronal death using a neuronal cell line that allows inducible p25 expression. In this system, no sign of apoptosis was seen before 24 hours of p25 induction. Thus, at that time, cell-cycle-regulatory proteins were analysed by immunoblotting and some of them showed a significant deregulation. Interestingly, after time-course experiments, the earliest feature correlated with p25 expression was the phosphorylation of the retinoblastoma protein (Rb). Indeed, this phosphorylation was observed 6 hours after p25 induction and was abolished in the presence of a Cdk5 inhibitor, roscovitine, which does not inhibit the usual Rb cyclin-D kinases Cdk4 and Cdk6. Furthermore, analyses of levels and subcellular localization of Cdk-related cyclins did not reveal any change following Cdk5 activation, arguing for a direct effect of Cdk5 activity on Rb protein. This latter result was clearly demonstrated by in vitro kinase assays showing that the p25-Cdk5 complex in our cell system phosphorylates Rb directly without the need for any intermediary kinase activity. Hence, Rb might be an appropriate candidate that connects Cdk5 to cell-cycle deregulation during neuronal cell death.

Key words: Apoptosis, Cell cycle, E2F-responsive genes, SKNSH-SY5Y neuroblastoma cells

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