CMGC kinases and Cancer

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Sammanfattning

A decade after identification of the human kinome, only a fraction of the kinome has been systematically studied. This clearly illustrates the lack of knowledge regarding the functions and cellular effects that these proteins have in the establishment of cellular phenotypes. Surprisingly, recent evidence suggests that approximately 23% of all kinase genes were estimated to function as cancer genes.
The overall aim of this thesis project was to shed light on the mechanisms controlling protein kinase activity and function, particularly in human cancers. A global and comprehensive interactomics analysis of the signaling networks of the evolutionarily conserved CMGC-protein kinase family, consisting of cyclin-dependent kinases [CDK], mitogen-activated protein kinases [MAPK], glycogen synthase kinases [GSK3] and CDC-like kinases [CLK]) was performed. From this physical and functional interaction analysis, hundreds of novel interactions, kinase-substrate relationships and previously unknown links to human diseases, such as cancer were identified. The unprecedented sensitivity and specificity of this approach was also illustrated, and highlighted, for example, by the purification and identification of the complete translational co-activator complex (the Mediator complex) with two of the CMGC kinases (CDK8 and CDK19). At the same time, the Mediator complex was identified mutated in benign uterine human tumors (uterine leiomyomas). To further deepen the understanding of the role of CDK8 and CDK19 kinases in controlling human disease pathways, we studied the functional role of two MED12 mutations in uterine leiomyoma and prostate cancer. Based on these studies, MED12 was found essential for the kinase activity of CDK8 in the context of the Mediator kinase module. Furthermore, disruption of the Mediator kinase module subunit interactions was shown as a common mechanism contributing to the formation of uterine leiomyoma. The MED12 mutants in leiomyoma and prostate cancer were shown functionally different. Finally, a novel MED12 nuclear localization signal was identified, and its importance in the correct nuclear localization of MED12 and subsequent proper assembly and function of the Mediator kinase module was experimentally proven.
The described results from the multidisciplinary studies clarify the cellular roles of CMGC kinases and Mediator subunits, facilitating the design of targeted future therapies/therapeutics against human diseases.
Originalspråkengelska
Tilldelande institution
  • Helsingfors universitet
Handledare
  • Varjosalo, Markku, Handledare
Tilldelningsdatum16 juni 2017
UtgivningsortHelsinki
Förlag
Tryckta ISBN978-951-51-3503-2
Elektroniska ISBN978-951-51-3504-9
StatusPublicerad - 16 juni 2017
MoE-publikationstypG5 Doktorsavhandling (artikel)

Vetenskapsgrenar

  • 1182 Biokemi, cell- och molekylärbiologi

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