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

Fox Chase Cancer Center, Filadelfia, Pennsylvania, United States
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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    ABSTRACT: The cell nucleus is a highly organized structure, playing an important role in gene regulation. Understanding the mechanisms that sustain this organization is therefore essential for understanding genome function. Centromeric regions (CR) of chromosomes have been known for years to adopt specific nuclear positioning patterns, but the significance of this observation is not yet completely understood. Here, using a combination of fluorescence in situ hybridization and immunochemistry on fixed human cells and high throughput imaging, we directly and quantitatively investigated the nuclear positioning of specific human CR. We observe differential attraction of individual CR toward both the nuclear border and the nucleoli, the former being enhanced in non-proliferating cells and the latter being enhanced in proliferating cells. Similar positioning patterns are observed in two different lymphoblastoid cell lines. Moreover the positioning of CR differs from that of non centromeric regions, and CR display specific orientations within chromosome territories. These results suggest the existence of not yet characterized mechanisms that drive the nuclear positioning of CR and therefore pave the way toward a better understanding of how CR affect nuclear organization. © 2015 by The American Society for Cell Biology.
    Full-text · Article · May 2015 · Molecular biology of the cell
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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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    ABSTRACT: Aging and carcinogenesis coincide with the accumulation of DNA damage and mutations in stem and progenitor cells. Molecular mechanisms that influence responses of stem and progenitor cells to DNA damage remain to be delineated. Here, we show that niche positioning and Wnt signaling activity modulate the sensitivity of intestinal stem and progenitor cells (ISPCs) to DNA damage. ISPCs at the crypt bottom with high Wnt/β-catenin activity are more sensitive to DNA damage compared to ISPCs in position 4 with low Wnt activity. These differences are not induced by differences in cell cycle activity but relate to DNA damage-dependent activation of Wnt signaling, which in turn amplifies DNA damage checkpoint activation. The study shows that instructed enhancement of Wnt signaling increases radio-sensitivity of ISPCs, while inhibition of Wnt signaling decreases it. These results provide a proof of concept that cell intrinsic levels of Wnt signaling modulate the sensitivity of ISPCs to DNA damage and heterogeneity in Wnt activation in the stem cell niche contributes to the selection of ISPCs in the context of DNA damage. © 2015 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
    Full-text · Article · Mar 2015 · The EMBO Journal
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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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    ABSTRACT: Cellular senescence is a stress response that accompanies stable exit from the cell cycle. Classically, senescence, particularly in human cells, involves the p53 and p16/Rb pathways, and often both of these tumor suppressor pathways need to be abrogated to bypass senescence. In parallel, a number of effector mechanisms of senescence have been identified and characterized. These studies suggest that senescence is a collective phenotype of these multiple effectors, and their intensity and combination can be different depending on triggers and cell types, conferring a complex and diverse nature to senescence. Series of studies on senescence-associated secretory phenotype (SASP) in particular have revealed various layers of functionality of senescent cells in vivo. Here we discuss some key features of senescence effectors and attempt to functionally link them when it is possible.
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