Apoptosis is a physiological mechanism by which pluricellular organisms get rid of damaged or useless cells. This is a biochemically active process that involves specialised biochemical pathways. Among these proteins are the Bcl2 family members which regulate the release of mitochondrial apoptotic mediators like Cytochrome C. The in vivo study of the Bcl2 family proteins using genetically modified mice has revealed that they are involved in the regulation of both cell death and cell division.
We have found that activation of the protein kinase Cdk2, originally involved in cell cycle regulation, is necessary for apoptosis of non-dividing cells like T-lymphocytes and neurons. The biochemical basis of these apparently opposite actions of Cdk2 rely on its association with specific activating subunits called Cyclins. Thus, during cell cycle regulation Cdk2 sequentially associates with Cyclins E and A, while we have found that during apoptosis it is activated by a different protein.
Mouse Cyclin O is induced during apoptosis in vivo and precedes Caspase-3 activation.
We have isolated a new Cyclin (Cyclin O) that is induced at the transcriptional level by intrinsic stimuli (DNA damage, glucocorticoids) but not by extrinsic stimuli (CD95/Fas/Apo1) in thymocytes preceding apoptosis.
Downregulation of Cyclin O abrogates apoptosis induded by intrinsic stimuli.
Cyclin O is a tightly regulated protein that may be involved in processes other than apoptosis, but it is not linked to cell cycle regulation. Given the fact that this new cyclin seems to be involved in regulation of cell death upstream of the known apoptosis mediators, we think that the characterisation of its function is of great interest to understand the upstream signalling of the intrinsic apoptotic stimuli and how its deregulation can contribute to tumorogenesis.