CIN by WNT: Growth Pathways, Mitotic Control and Chromosomal Instability in Cancer

Hadjihannas, Michel V.; Behrens, Jürgen

doi:10.4161/cc.5.18.3282

Cited by 31 publications

(22 citation statements)

References 64 publications

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“…In our reprogramming experiments we found that ectopic WNT signal activation with Wnt3a promoted genomic instability during reprogramming of PORCN mutant cells. The association between ectopic WNT signaling and chromosomal instability had been described previously but only in cells with compromised genomic integrity, such as HCT116, SW480 and HeLa cells (Hadjihannas and Behrens, 2006; Tighe et al, 2007). Additional studies found that mouse embryonic stem cells harboring mutations in the APC gene, a negative regulator of WNT/β-catenin signaling, exhibit defects in chromosome segregation, leading to highly variable chromosome numbers (Aoki et al, 2007; Fodde et al, 2001; Kaplan et al, 2001).…”

Section: Discussionmentioning

confidence: 71%

“…Previous studies have linked aberrant WNT signaling to chromosomal instability (Aoki et al, 2007; Fodde et al, 2001; Hadjihannas and Behrens, 2006; Hadjihannas et al, 2006; Kaplan et al, 2001; Tighe et al, 2007). To circumvent this problem, we isolated FDH-iPS cell colonies from reprogrammed cultures derived in the presence of CHIR, which can be carefully dosed and is more stable over longer periods than Wnt3a protein (Figure S4D).…”

Section: Resultsmentioning

confidence: 99%

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A Rare Human Syndrome Provides Genetic Evidence that WNT Signaling Is Required for Reprogramming of Fibroblasts to Induced Pluripotent Stem Cells

et al. 2014

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SUMMARY WNT signaling promotes the reprogramming of somatic cells to an induced pluripotent state. We provide genetic evidence that WNT signaling is a requisite step during the induction of pluripotency. Fibroblasts from individuals with Focal Dermal Hypoplasia (FDH), a rare genetic syndrome caused by mutations in the essential WNT processing enzyme PORCN, fail to reprogram using standard methods. This blockade in reprogramming is overcome by ectopic WNT signaling and by PORCN overexpression, thus demonstrating that WNT signaling is essential for reprogramming. The rescue of reprogramming is critically dependent on the level of WNT signaling: steady baseline activation of the WNT pathway yields karyotypically normal iPS cells, whereas daily stimulation with Wnt3a produces FDH-iPS cells with severely abnormal karyotypes. Therefore, although WNT signaling is required for cellular reprogramming, inappropriate activation of WNT signaling induces chromosomal instability, highlighting the precarious nature of ectopic WNT activation, and its tight relationship with oncogenic transformation.

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Section: Discussionmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

A Rare Human Syndrome Provides Genetic Evidence that WNT Signaling Is Required for Reprogramming of Fibroblasts to Induced Pluripotent Stem Cells

et al. 2014

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“…Deregulation of canonical Wnt signaling and misexpression of core Wnt pathway components occur frequently and are causal in the initiation and progression of cancer (1). Wnt ligand-stimulated activation of the canonical pathway results in translocation of the h-catenin transcriptional complex from the cytoplasm to the nucleus where it associates with, and activates, T-cell factor/lymphoid enhancer-binding factor-1 -dependent transcription.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic Activation of the Human Pygopus2 Promoter by E74-Like Factor-1

Andrews¹,

Kennedy²,

Popadiuk

et al. 2008

Molecular Cancer Research

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Pygopus is a component of the T-cell factor/B-catenin transcriptional complex essential for activation of Wnt target genes and is also required for cell regulation in the absence of Wnt signaling. Human Pygopus2 (hPygo2) is overexpressed in a high proportion of breast and epithelial ovarian malignant tumors and is required for the growth of several cell lines derived from these carcinomas. The mechanisms regulating hPygo2 gene activation, however, are unknown. Here, we have determined cis-and trans-interacting factors responsible for hPygo2 expression in cancer. The minimal region required for a maximal 109-fold activation of the hPygo2 promoter in MCF-7 breast cancer cells is 48 bp upstream of the start of transcription. Within 25 bp of the transcriptional start, there are two overlapping tandem Ets transcription factor -binding sites, which are critical for hPygo2 promoter activity. In vitro DNA pull-down assays and proteomic analyses identified the Ets family members Elk-1 and E74-like factor-1 (Elf-1) as potential hPygo2 promoter binding factors, whereas in vivo chromatin immunoprecipitation assays verified that only Elf-1 specifically bound to the hPygo2 promoter in MCF-7 cells. Modulation of elf-1 in MCF-7 cells by silencing via RNA interference or overexpression caused a corresponding decrease or increase, respectively, in hPygo2 promoter activity. Overexpression of Elf-1 in HeLa cells, in which Elf-1 is expressed at a lower level than in MCF-7 cells, caused a 4-fold increase in endogenous hPygo2 mRNA levels. These results provide new evidence that Elf-1 is involved in transcriptional activation of hPygo2. Like hPygo2, previous studies implicated Elf-1 in breast and ovarian cancer and our present findings suggest that the oncogenic requirement of hPygo2 is fulfilled, in part, by Elf-1. (Mol Cancer Res 2008;6(2):259 -66)

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“…In this respect it is worth noting that mutations in Wnt components result in chromosomal instability, which is a hallmark of many cancer types. 9 Orientation of the mitotic spindle is also a key regulator of asymmetric cell division as it sets the division plane at cytokenesis. Since Wnt is known to control asymmetric cell division, another possibility is that phosphorylation of LRP6 regulates differential localisation of cellular components at mitosis, thus influencing the fate of daughter cells after cytokenesis.…”

mentioning

confidence: 99%

The cell cycle and Wnt

Davidson¹

2010

Cell Cycle

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CIN by WNT: Growth Pathways, Mitotic Control and Chromosomal Instability in Cancer

Cited by 31 publications

References 64 publications

A Rare Human Syndrome Provides Genetic Evidence that WNT Signaling Is Required for Reprogramming of Fibroblasts to Induced Pluripotent Stem Cells

A Rare Human Syndrome Provides Genetic Evidence that WNT Signaling Is Required for Reprogramming of Fibroblasts to Induced Pluripotent Stem Cells

Oncogenic Activation of the Human Pygopus2 Promoter by E74-Like Factor-1

The cell cycle and Wnt

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