학술논문
Novel molecular insights into trans-differentiation and tumorigenesis by regulating cell cycle kinases in human cells
Document Type
Dissertation/ Thesis
Author
Source
Subject
Language
English
Abstract
Part1. Cyclin-dependent kinase 4 signaling acts as a molecular switch between syngenic differentiation and neural trans-differentiation in human mesenchymal stem cellsMultipotent mesenchymal stem/stromal cells (MSCs) are capable of differentiating into a variety of cell types from different germ layers. However, the molecular and biochemical mechanisms underlying the trans-differentiation of MSCs into specific cell types still need to be elucidated. In this study, we unexpectedly found that treatment of human adipose- and bone marrow-derived MSCs with cyclin-dependent kinase (CDK) inhibitor, in particular CDK4 inhibitor, selectively led to trans-differentiation into neural cells with a high frequency. Specifically, targeted inhibition of CDK4 expression using recombinant adenovial shRNA induced the neural trans-differentiation of human MSCs. However, the inhibition of CDK4 activity attenuated the syngenic differentiation of human adipose-derived MSCs. Importantly, the forced regulation of CDK4 activity showed reciprocal reversibility between neural differentiation and dedifferentiation of human MSCs. Together, these results provide novel molecular evidence underlying the enrichment of neural stem/progenitor pool of human MSCs human MSCs through regulation of Smad-STAT and Hippo pathway signaling via CDK4 kinase activity.
Part2. Brain expressed X-linked gene 4 is a novel oncogene which deregulates microtubule dynamics and induces aneuploidy transformation.Five brain expressed X-linked (Bex) gene members (Bex4-4) are arranged in tandem on chromosome X, and are highly conserved across diverse species. However, the function and role of Bex4 proteins particularly in relation to disease areas are largely unknown. This study represents a first attempt to demonstrate the molecular function of Bex4 during tumorigenesis. It was found Bex4 expression increased the proliferating potential and the growth of tumors. Furthermore, Plk4-mediated phosphorylation regulated the Bex4 protein, and Bex4 expression allowed abnormal mitotic cells to adapt to an aneuploid status, whereas Bex4 depletion reduced the aneuploid population via BubR1 or Mad2 depletion and significantly enhanced apoptotic cell death. Our findings suggest that Bex4 deregulates microtubule dynamics and acts as a novel oncogene by enabling the acquisition of chromosomal instability.
Part2. Brain expressed X-linked gene 4 is a novel oncogene which deregulates microtubule dynamics and induces aneuploidy transformation.Five brain expressed X-linked (Bex) gene members (Bex4-4) are arranged in tandem on chromosome X, and are highly conserved across diverse species. However, the function and role of Bex4 proteins particularly in relation to disease areas are largely unknown. This study represents a first attempt to demonstrate the molecular function of Bex4 during tumorigenesis. It was found Bex4 expression increased the proliferating potential and the growth of tumors. Furthermore, Plk4-mediated phosphorylation regulated the Bex4 protein, and Bex4 expression allowed abnormal mitotic cells to adapt to an aneuploid status, whereas Bex4 depletion reduced the aneuploid population via BubR1 or Mad2 depletion and significantly enhanced apoptotic cell death. Our findings suggest that Bex4 deregulates microtubule dynamics and acts as a novel oncogene by enabling the acquisition of chromosomal instability.