Interplay between the p53 tumor suppressor protein family and Cdk5 |
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Authors: | Gerald Schmid Joanna B Strosznajder Józefa Węsierska-G≸dek |
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Institution: | 1. Department of Medicine 1, Institute of Cancer Research and Cell Cycle Regulation Group, Medical University of Vienna, Vienna, Austria 2. LMU Klinikum Grosshadern, Experimentelle Forschung Chirurgie, Muenchen, Germany 3. Centre of Experimental and Clinical Medicine, Polish Academy of Science, Warsaw, Poland
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Abstract: | Cyclin-dependent kinases (Cdks) play a key role in orchestrating the coordination of cell cycle progression in proliferating
cells. The escape from the proper, control of the cell cycle by the upregulation of cyclins or aberrant activation of Cdks
leads to malignant transformation. In quiescent cells and/or terminally differentiated cells, the expression pattern and activity
of Cdks is altered. In postmitotic neurons, expression of mitotic kinases is downregulated, whereas Cdk5 expression becomes
upregulated. Similarly to other Cdks, free Cdk5 displays no enzymatic activity and requires complex formation with a specific
regulatory subunit. Two activators of Cdk5 have been identified. p35 and its isoform p39 bind to, and thereby activate, Cdk5.
Unlike mitotic kinases, Cdk5 does not require activating phosphorylation within the T-loop. Because p35 is a short-lived protein,
the p35/Cdk5 complexes are unstable. The stability of the p35 protein is regulated by its Cdk5-mediated phosphorylation of
p35. Activated p35/Cdk5 kinase phosphorylates numerous physiological targets.
The proper phosphorylation of the most important substrates, such as τ protein and neurofilament H, is essential for the correct
regulation of the cytoskeletal organization, thereby regulating cell adhesion, motility, and synaptic plasticity. Moreover,
Cdk5 regulates the activity of the p53 tumor suppressor via phosphorylation. p53 is upregulated in multiple neuronal death
paradigms, including hypoxia, ischemia, and excitotoxicity, and plays a key role in the induction of apoptosis. On the other
hand, an abnormally high expression and elevated activity of Cdk5 was observed in neurodegenerative diseases, suggesting the
application of Cdk inhibitors for their therapy. Considering the action of some Cdk inhibitors on the expression and activity
of the p53 protein, their therapeutic efficacy must be carefully evaluated. |
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