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From structural to molecular systems biology: experimental and computational approaches to unravel mechanisms of kinase activity regulation in cancer and neurodegeneration

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Regulation of kinase activities plays a critical role in the phase-specific events that characterize cell cycle progression. Multiple signals such as direct or indirect activators and inhibitors influence timing of their expression, therefore, defining precise temporal windows of their regulatory activity. ...

Regulation of kinase activities plays a critical role in the phase-specific events that characterize cell cycle progression. Multiple signals such as direct or indirect activators and inhibitors influence timing of their expression, therefore, defining precise temporal windows of their regulatory activity. This ensures a tight control mechanism which is partially or completely lost during processes of cancer and neurodegeneration. Biochemical, genetic and epidemiologic evidence has been provided over the last years linking a number of genes involved in both tumor development and apoptosis-related diseases. Although tumorigenesis and neurodegeneration are different pathologies, common factors and overlapping molecular pathways have been identified in the generation and progression of these human disorders, often with complementary relationships. Of particular interest is that dysregulation of genes implicated in the control of cell cycle progression is a hallmark of tumorigenesis and the same defects seem to contribute to the degeneration of post-mitotic neurons under apoptotic conditions. Recent evidences suggest that also in budding yeast the apoptotic process is closely related to deregulation of cell cycle events, where inactivation or down-regulation of kinase activities suggest a possible, but still not proved, connection between cell cycle events and apoptosis. Therefore, to study how eukaryotic cell cycle dysregulation leads to tumorogenesis and apoptotic phenotypes observed in neurodegenerative pathologies represents a challenge in Systems Biology, with the aim to elucidate properties or phenotypes that emerge through interactions of molecules in complex biological networks. Multiscale modeling approaches are presented where complementary experimental and computational approaches are employed to investigate structure, function and temporal dynamics of the kinase activities in eukaryotes. A Systems Biology point of view is applied here from budding yeast to mammalian cells, where fundamental processes of cell cycle regulation are highly conserved.


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