title: GSK3β activity is essential for senescence-associated heterochromatin foci (SAHF) formation induced by HMGA2 in WI38 cells.
abstract: Cellular senescence is an irreversible form of cell cycle arrest, which is often characterized by domains of facultative heterochromatin substructures also known as senescence-associated heterochromatin foci (SAHF). SAHF assembly is likely mediated through the downregulation of the Wnt pathway, which inhibits Glycogen Synthase Kinase 3 Beta (GSK3β) in cells undergoing replicative senescence. Alternatively, High Mobility Group AT-Hook 2 (HMGA2) can also induce SAHF formation in primary cells, through a process in which the involved cell signaling pathway is unknown. Accordingly, it is important to determine whether GSK3β and the Wnt pathway are necessary during HMGA2-induced SAHF formation. In this study, we developed a senescence model for SAHF assembly in WI38 cell through ectopic expression of HMGA2. In this model, typical senescent features were identified, including elevated SA-β-galactosidase staining and the downregulation of the Wnt pathway. We also showed that the GSK3β inhibitor LiCl can partly disable SAHF formation through the HMGA2 overexpression in WI38 cells. However, the disabled SAHF formation resulting from the inactivity of GSK3β in our senescence model cannot be restored through ectopic overexpression of Catenin Beta 1 (CTNNB1), a downstream transcription factor of the Wnt pathway. This indicates that the GSK3β activity alone, and not those of downstream target genes, is crucial for the HMGA2-induced SAHF formation following the downregulation of the Wnt pathway.
authors.affiliation: The Institute of Audiology and Balance Science of Xuzhou Medical University Xuzhou 221004, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Shi
authors.affiliation: Institute of Bioengineering of Jinan University Guangzhou 510632, China.
authors.forename: Baoqing
authors.initials: B
authors.lastname: Tian
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University Changchun 130024, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Ma
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University Changchun 130024, China.
authors.forename: Lingxia
authors.initials: L
authors.lastname: Liu
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University Changchun 130024, China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.affiliation: The Institute of Audiology and Balance Science of Xuzhou Medical University Xuzhou 221004, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Na
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Science, Peking University Beijing 100871, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University Changchun 130024, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Clinical Hearing Center of Affiliated Hospital of Xuzhou Medical University Xuzhou 221006, China.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Qiao
keywords: GSK3β; HMGA2; SAHF; Wnt2