p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death
- 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.
Author: | Malika Hamdane, Alexis Bretteville, Anne-Véronique Sambo, Katharina SchindowskiORCiDGND, Séverine Bégard, André Delacourte, Philippe Bertrand, Luc Buée |
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URN: | urn:nbn:de:hebis:30-34489 |
DOI: | https://doi.org/10.1242/jcs.01724 |
Parent Title (German): | Journal of Cell Science |
Document Type: | Article |
Language: | English |
Year of Completion: | 2005 |
Year of first Publication: | 2005 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2006/11/29 |
Tag: | Apoptosis; Cell cycle; E2F-responsive genes; SKNSH-SY5Y neuroblastoma cells |
Volume: | 118 |
First Page: | 1291 |
Last Page: | 1298 |
Source: | In: Journal of Cell Science 2005 Mar 15;118(Pt 6):1291-8. Epub 2005 Mar 1. ; doi: 10.1242/jcs.01724 |
HeBIS-PPN: | 188841245 |
Institutes: | Biochemie, Chemie und Pharmazie / Pharmazie |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Sammlungen: | Sammlung Biologie / Sondersammelgebiets-Volltexte |
Licence (German): | Deutsches Urheberrecht |