The APC tumour suppressor has a nuclear export function

Rosin‐Arbesfeld, Rina; Townsley, Fiona M.; Bienz, Mariann

doi:10.1038/35023016

Cited by 325 publications

(312 citation statements)

References 40 publications

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“…Normal APC function seems to be critical for the colorectal mucosal epithelium, since APC mutations are often found in the earliest stages of colorectal tumorigenesis. The APC protein has been demonstrated in several subcellular compartments including the cytoplasm, nucleus and adhesive cadherincatenin junctions (Rosin-Arbesfeld et al, 2000). In the current study, cytoplasmic and cell border staining of the overlying epithelium (OSE) was present, while nuclear staining was absent.…”

Section: Discussionmentioning

confidence: 46%

Wnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β

et al. 2003

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Beta-catenin is involved in both cell -cell adhesion and in transcriptional regulation by the Wingless/Wnt signalling pathway. Alterations of components of this pathway have been suggested to play a central role in tumorigenesis. The present study investigated, by immunohistochemistry and immunoblotting, the protein expression and localisation of b-catenin, adenomatous polyposis coli (APC), glycogen synthase kinase 3b (GSK3b) and lymphocyte enhancer factor-1 (Lef-1) in normal human ovaries and in epithelial ovarian tumours in vivo and in vitro. Immortalised human ovarian surface epithelium and ovarian cancer cell cells (OVCAR-3) expressed b-catenin, APC, GSK3b and Lef-1. Nuclear staining of b-catenin and Lef-1 were demonstrated only in OVCAR-3 cells. There were significant increases of b-catenin and GSK3b, while APC was reduced in ovarian cancer compared to the normal ovary. Beta-catenin and Lef-1 were coimmunoprecipitated in ovarian tumours, but not in the normal ovary. Nuclear localisation of b-catenin or Lef-1 could not be demonstrated in the normal ovary or in the ovarian tumours. The absence of nuclear localisation of b-catenin could be due to an increased binding to the cadherin -a-catenin cell adhesion complex. In fact, we have earlier reported an increased expression of E-cadherin in ovarian adenocarcinomas. In summary, this study demonstrates an increase in the expression of components of the Wingless/Wnt pathway in malignant ovarian tumours. The increase suggests a role for this signalling pathway in cell transformation and in tumour progression. However, it remains to be demonstrated whether it is an increased participation of b-catenin in transcriptional regulation, or in the stabilisation of cellular integrity, or both, that is the crucial event in ovarian tumorigenesis.

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Section: Discussionmentioning

confidence: 46%

Wnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β

et al. 2003

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“…In colorectal cancer it has been previously noted that the majority of the somatic APC mutations map to the MCR. In this region, the presence of nuclear export signal (NES) sequences was reported (Rosin-Arbesveld et al, 2000) and their importance for the APC ability to export and degrade nuclear β-catenin was shown. It appears that the truncated APC proteins usually bind to β-catenin but fail to export it to the cytoplasm.…”

Section: Resultsmentioning

confidence: 99%

APCgermline mutations identified in Czech patients with familial adenomatous polyposis

et al. 2002

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Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited predispositionto colorectal cancer, which is caused by germline mutations in the adenomatous polyposis coli (APC) gene. The APC mutations have been investigated in 46 Czech unrelated FAP families and 9 suspected FAP families using DGGE analysis and direct DNA sequencing. We found 25 germline APC mutations and identified 11 which were not previously reported. Of the identified mutations, 10 were 1 to 5 bp deletions, four were 1 bp insertions and six were nonsense, all leading to the formation of premature stop codon. In addition, we detected two mutations in the splice-donor region of APC intron 11, one missense and two samesense mutations. Phenotypes of patients with known and novel types of mutations are presented and discussed.

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“…A surprisingly high number of cytoplasmic Wnt regulators are shuttling proteins that distribute both, in the cytoplasm and the nucleus, where they may, directly or indirectly, interact with β-catenin and modulate its transcriptional activity [21]. This holds especially for the β-catenin antagonists APC [22,23], Axin [24,25] and the kinases GSK3 [26][27][28] and CK1 [21].…”

Section: The Wnt Signalling Pathwaymentioning

confidence: 99%

“…APC is a large ∼ 310 kDa protein. It exhibits at least two NES interacting with the CRM1 nuclear export factor and has been proven to shuttle between cytoplasm and nucleus [22,23], but the functional relevance of this is still controversial [40][41][42]. It was proposed that the nuclear export of APC controls the level and hence the transcriptional activity of nuclear β-catenin [38,39].…”

Section: β-Catenin and Apc Shuttle Using Different Mechanismsmentioning

confidence: 99%

“…The nucleo-cytoplasmic shuttling of APC, however, depends on indirect interaction with the NPCs and occurs in both directions by facilitated transport [22,23]. In our approach, we investigate the influence of nucleo-cytoplasmic shuttling of APC on the output of the Wnt signalling by studying different shuttling mechanisms:…”

Section: Nucleo-cytoplasmic Shuttling Of β-Catenin and Apcmentioning

confidence: 99%

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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 tumour suppressor has a nuclear export function

Cited by 325 publications

References 40 publications

Wnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β

Wnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β

APCgermline mutations identified in Czech patients with familial adenomatous polyposis

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

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