Downregulation of Wnt Signaling Is a Trigger for Formation of Facultative Heterochromatin and Onset of Cell Senescence in Primary Human Cells

Department of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Molecular Cell (Impact Factor: 14.02). 08/2007; 27(2):183-96. DOI: 10.1016/j.molcel.2007.05.034
Source: PubMed


Cellular senescence is an irreversible proliferation arrest of primary cells and an important tumor suppression process. Senescence is often characterized by domains of facultative heterochromatin, called senescence-associated heterochromatin foci (SAHF), which repress expression of proliferation-promoting genes. Formation of SAHF is driven by a complex of histone chaperones, HIRA and ASF1a, and depends upon prior localization of HIRA to PML nuclear bodies. However, how the SAHF assembly pathway is activated in senescent cells is not known. Here we show that expression of the canonical Wnt2 ligand and downstream canonical Wnt signals are repressed in senescent human cells. Repression of Wnt2 occurs early in senescence and independently of the pRB and p53 tumor suppressor proteins and drives relocalization of HIRA to PML bodies, formation of SAHF and senescence, likely through GSK3beta-mediated phosphorylation of HIRA. These results have major implications for our understanding of both Wnt signaling and senescence in tissue homeostasis and cancer progression.

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Available from: Banumathy Gowrishankar, Mar 13, 2014
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    • "The expression of 142 genes was increased or decreased more than twofold in progerin vs lamin A expressing cells (Figure 1G). Many of these gene expression changes were associated with senescence, including a reduction of Wnt2 (Ye et al., 2007), increased expression of matrix metalloproteinases (Kang et al., 2003) and plasminogen activator inhibitor-1 (PAI-1) (Kortlever et al., 2006). Expression of TERT prevented nearly all these changes in the differentially expressed genes, and restored the gene expression profile to that seen in cells not expressing progerin (Figure 1H). "
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    Molecular biology of the cell 05/2015; 26(13). DOI:10.1091/mbc.E14-05-1002 · 4.47 Impact Factor
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    • "Alterations in Wnt signaling were implicated in aging of adult tissues (Brack et al, 2007; Liu et al, 2007; Ye et al, 2007). "
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    • " laboratory ( Zhang et al . 2005 , 2007 ; Ye et al . 2007a , b ) have shown that , as an early event in senescence , translocation of the HIRA histone chaperone complex to PML NBs is required for SAHF formation . They also found that the relocaliza - tion of HIRA to PML bodies is driven by down - regulation of the canonical Wnt signaling pathway ( Ye et al . 2007a ) ."
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