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Léa Ziercher

Functional study of the regulating subunit of the protein kinase CK2 in murin embryonic stem cells: Cellular survival, oligodendrogenesis and cancerogenesis

Published on 11 October 2007


Thesis presented October 11, 2007

Abstract:
The protein kinase CK2 is a dynamic complex of 2 catalytic subunits
α and ß of a dimer of regulatory subunit ß. Crystallographic structure of the CK2ß dimer suggests the existence of functional domains involved in the regulating function of the dimer towards the catalytic subunits, as well as in interactions with various protein partners. The CK2ß dimer would represent a molecular platform, linking the protein to the center of signaling pathway networks.
The knockout of the murine CK2ß gene results in a defect of embryonic stem cell viability. We studied the in vitro function of different functional domains with the ​use of « death-rescue » cellular model or by additional transgenesis of mutants CK2ß.
This cellular system is based on a conditional CK2ß gene knockout strategy using murine​ embryonic stem cells (ES cells). The abolition of the endogenous gene expression is lethal for ES cells and the exogenous expression of the wild-type protein CK2ß rescues their viability. This « death-rescue » model allows us to study the involvement of various domains of CK2ß in the survival, the proliferation and the differentiation of embryonic stem cells.
In parallel, the conditional targeted knockout in murine neural precursors demonstrated that CK2ß is a key element in signaling pathways that control oligodendrogenesis. The differentiation of nullizygotes ES cells expressing the wild-type exogenous protein reveals that wild-type CK2ß rescues the oligodendrocyte lineage. We also showed that some CK2ß domains, linked to dimer regulatory functions, are crucial structure determinants for the proliferation of neural stem cells and their progression into the oligodendrocyte lineage.

Keywords:
Protein kinase CK2, « death-rescue » cellular model, embryonic stem cell, oligodendrogenesis

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