The APC tumor suppressor counteracts β-catenin activation and H3K4 methylation at Wnt target genes

Sierra, J M; Yoshida, Tatsushi; Joazeiro, Claudio A.P.; Jones, Katherine A.

doi:10.1101/gad.1385806

Cited by 355 publications

(424 citation statements)

References 60 publications

(66 reference statements)

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“…Among the TCF family proteins, TCF-3 and TCF-4 have been shown to contain CtBP binding domains and to interact with mammalian CtBP proteins in vitro, but other members such as LEF-1 and TCF-1 do not require CtBP (Brannon et al, 1999;Roose and Clevers, 1999;Valenta et al, 2003). Additionally, CtBPs can also interact with APC tumor suppressor protein to divert active nuclear ␤-catenin away from TCFs (Hamada and Bienz, 2004;Sierra et al, 2006). Furthermore, CtBP has been recently shown to directly activate or repress Wnt target genes in a TCF-independent manner in Drosophila, increasing the complexity of the Wnt signaling mechanism (Fang et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…APC has also been shown to counteract ␤-catenin activity by directly mediating repression of Wnt target genes through its ability to initiate recruitment of transcriptional corepressor CtBP and chromatin remodeling complexes (Sierra et al, 2006). In addition, recent studies suggested that the oncogenic activity of ␤-catenin may include its ability to influence premRNA splicing, thus allowing the production of cancer-associated splicing variants (Sato et al, 2005;Lee et al, 2006;Shitashige et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Although the signaling pathway or the mechanism orchestrating these coordinated alterations in gene expression are still unknown, PNN was shown to directly interact with CtBP and have an effect on the activity of E-cadherin promoter (Alpatov et al, 2004). Because CtBP has been closely implicated in Wnt signaling (Chinnadurai, 2002;Hamada and Bienz, 2004;Sierra et al, 2006) and expression of E-cadherin is often negatively regulated by Wnt signaling in development and cancer (Jamora et al, 2003;Yook et al, 2005), PNN's ability to interact with CtBP, along with PNNmediated phenotypic changes in adhesion, proliferation, and motility, may suggest possible involvement of PNN in Wnt signaling. In addition, PNN interacts with several pre-mRNA splicing factors by means of its RS domain and plays a role in alternative splicing Zimowska et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Role of Pinin in neural crest, dorsal dermis, and axial skeleton development and its involvement in the regulation of Tcf/Lef activity in mice

Joo

Lee

Munguba

et al. 2007

Developmental Dynamics

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Previous in vitro studies have indicated multiple and varied roles of Pinin (PNN); however, its in vivo role has remained unclear. Here, we report generation of null, hypomorphic, and conditional Pnn alleles in mice. We found that insertion of neomycin-resistance cassette into intron 8 of Pnn resulted in knockdown of Pnn, which allowed Pnn hypomorphic embryos to pass peri-implantation lethality. These mice are lethal at perinatal stages and exhibit defects in the cardiac outflow tract, palate, dorsal dermis, and axial skeleton. Since Wnt/␤-catenin signaling has been shown to play pivotal roles in development of all tissues affected by Pnn hypomorphism, we speculated that Pnn may affect Wnt/␤-catenin signaling. Supporting this view, we demonstrate abnormal activities of Tcf/Lef transcription factors, and alterations in ␤-catenin level in multiple Pnn hypomorphic tissues. Taken together, the data suggest that Pnn plays important roles during mouse development through its involvement in regulation of Tcf/Lef activity. Developmental Dynamics 236: 2147-2158, 2007.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of Pinin in neural crest, dorsal dermis, and axial skeleton development and its involvement in the regulation of Tcf/Lef activity in mice

Joo

Lee

Munguba

et al. 2007

Developmental Dynamics

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“…MLL N also contains a CxxC domain, which specifically binds to unmethylated DNA. 29 Transcription factors such as p53 and CTNNB1(b-catenin) are most likely to recruit the MLL complex to initiate RNA synthesis, 26,30 and specific genes, such as the HOX genes, seem to be more dependent on the MLL complex for chromatin modification during transcription than others. 31,32 In MLL rearrangements the breakpoint in MLL is highly conserved and all fusion partners are fused in frame, leading to a gain of function of the MLL complex.…”

Section: Etiology Of Mll Rearrangementsmentioning

confidence: 99%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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Translocations involving the mixed-lineage leukemia (MLL) gene, localized at 11q23, comprise 15 to 20% of all pediatric acute myeloid leukemia (AML) cases. This review summarizes current knowledge about the etiology, biology, clinical characteristics and differences in outcome in MLL-rearranged pediatric AML. Furthermore, we discuss the role of cooperating events in MLL-rearranged pediatric AML, and future therapeutic strategies to improve outcome. We conclude that MLL-rearranged pediatric AML is a heterogeneous disease, and prognosis depends on various factors, for example, translocation partner, age, WBC and additional cytogenetic aberrations. The relationship of outcome with specific translocation partners requires that they be searched for in the diagnostic work-up of AML. To achieve further improvements in outcome, unraveling the biology of MLL-rearranged pediatric AML is warranted.

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“…However, it has been demonstrated that phosphorylation enhances the ability of APC to interact with β-catenin in vitro [49]. Moreover, Sierra et al [50] concluded from their experiments that β-catenin cannot bind unphosphorylated APC efficiently and that CK1 phosphorylation of APC might induce high-affinity binding to β-catenin and even trigger its dissociation from LEF/TCF. Seo and Jho proposed in [51] that accumulation of cytoplasmic β-catenin induces phosphorylation of APC and that phosphorylated APC retains β-catenin.…”

Section: The Impact Of the Dissociation Constantsmentioning

confidence: 99%

Nucleo-cytoplasmic shuttling of APC can maximize β‐catenin/TCF concentration

Schmitz¹,

Rateitschak²

2011

Journal of Theoretical Biology

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Abstractβ-catenin is the key player of the canonical Wnt pathway. Its activity is mainly regulated via protein degradation.In the nucleus, its interaction with TCF initiates target gene expression. Although the functional relevance is unclear, it has been shown that β-catenin antagonists are also capable of nucleo-cytoplasmic shuttling. The focus of our systems biology analysis lies on the β-catenin subcellular distribution regulated by the antagonist and scaffolding protein APC. We address the following questions: Can the concentration of the transcription factor complex [β-catenin/TCF], which is considered as the output of the pathway, be maximized by APC nucleo-cytoplasmic shuttling and how is retention of β-catenin by APC influencing this output?We established a mathematical model based on experimental findings to examine the influence of nucleocytoplasmic shuttling of APC and retention of β-catenin by APC on the output of the pathway. The model is based on ordinary differential equations and includes protein shuttling between the two compartments nucleus and cytoplasm as well as protein complex formation in each compartment. We discuss how the steady state concentration of [β-catenin/TCF] is influenced by APC shuttling and retention. The analysis of the model shows that the breakdown of β-catenin cytoplasmic retention induced by APC shuttling can enhance nuclear accumulation of β-catenin and hence maximize the output of the pathway.Using mathematical modelling, we demonstrate that in certain parameter ranges, the steady state concentration of [β-catenin/TCF] benefits from APC shuttling. The inhibitory effect of APC is alleviated due to shuttling of APC. Surprisingly, our study therefore indicates that the nucleo-cytoplasmic shuttling of APC can have a beneficial effect on the output of the pathway in steady state, although APC is in general a β-catenin antagonizing protein.Furthermore, we show that saturated protein translocation can under certain conditions be modelled by pure diffusion. A difference in the shuttling rate constants of sufficient orders of magnitude leads to an accumulation in either compartment, which corresponds to saturation in translocation.

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The APC tumor suppressor counteracts β-catenin activation and H3K4 methylation at Wnt target genes

Cited by 355 publications

References 60 publications

Role of Pinin in neural crest, dorsal dermis, and axial skeleton development and its involvement in the regulation of Tcf/Lef activity in mice

Role of Pinin in neural crest, dorsal dermis, and axial skeleton development and its involvement in the regulation of Tcf/Lef activity in mice

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

Nucleo-cytoplasmic shuttling of APC can maximize β‐catenin/TCF concentration

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