Cited by 343Wnt/β-catenin signaling in development and cancerGenetic factors in colorectal cancerSignaling Pathways in Disease

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The APC tumour suppressor has a nuclear export function

Rosin-Arbesfeld, Rina, Townsley, Fiona, Bienz, Mariann·2000·Nature

DOI 10.1038/35023016

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Abstract

The adenomatous polpyposis coli (APC) protein is mutated in most colorectal tumours. Nearly all APC mutations are truncations, and many of these terminate in the mutation cluster region located halfway through the protein. In cancer cells expressing mutant APC, beta-catenin is stabilized and translocates into the nucleus to act as a transcriptional co-activator of T-cell factor. During normal development, APC also promotes the destabilization of beta-catenin and Drosophila Armadillo. It does so by binding to the Axin complex which earmarks beta-catenin/Armadillo for degradation by the proteasome pathway. APC has a regulatory role in this process, which is poorly understood. Here we show that APC contains highly conserved nuclear export signals 3' adjacent to the mutation cluster region that enable it to exit from the nucleus. This ability is lost in APC mutant cancer cells, and we provide evidence that beta-catenin accumulates in the nucleus as a result. Thus, the ability of APC to exit from the nucleus appears to be critical for its tumour suppressor function.

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BackgroundInfluential
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Background
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Background
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BackgroundResultInfluential
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Background
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Background
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NEW EVIDENCE THAT NUCLEAR IMPORT OF ENDOGENOUS β‐CATENIN IS LEF‐1 DEPENDENT, WHILE LEF‐1 INDEPENDENT IMPORT OF EXOGENOUS β‐CATENIN LEADS TO NUCLEAR ABNORMALITIES
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BackgroundInfluential
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“Another important finding was that APC, a component of the degradation complex, was shown to function in nuclear export of Arm (Rosin-Arbesfeld et al. 2000), and in opposing transcriptional activation by the Arm/TCF complex (Sierra et al. 2006).”
Background
Density-dependent location and interactions of truncated APC and β-catenin
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BackgroundInfluential
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Background
Characterization of a beta-catenin nuclear localization defect in MCF-7 breast cancer cells
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“It is noteworthy that two reports published simultaneously, and describing the nuclear localisation of APC in SW480 cells (Henderson, 2000; Rosin-Arbesfeld et al, 2000) presented almost identical images despite one of them (Henderson, 2000) using APC(N15).”
Wnt/β‐catenin‐mediated transcriptional regulation
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Epithelial proliferation induces novel changes in APC expression
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“For example, nuclear APC has been found to sequester b-catenin and promote its nuclear export (Henderson, 2000; Neufeld et al., 2000b; Rosin-Arbesfeld et al., 2000).”
Background
Chibby suppresses growth of human SW480 colon adenocarcinoma cells through inhibition of β-catenin signaling
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“Nuclear APC can repress Wnt target gene expression both in vivo and in cultured cells (10,13,15,40).”
Background
Metastasis of Prostate Cancer
Ablin, R. J., & Mason, M. D. (2007) · Cancer metastasis · doi:10.1007/978-1-4020-5847-9 · Cited by 13
Selinexor and the Selective Inhibition of Nuclear Export: A New Perspective on the Treatment of Sarcomas and Other Solid and Non-Solid Tumors
Marretta, A. L., Lorenzo, G. D., Ribera, D., Cannella, L., von Arx, C., Bracigliano, A., Clemente, O., Tafuto, R., Pizzolorusso, A., & Tafuto, S. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13091522 · Cited by 11
“53, [13]), BRCA1 [14], cyclin D1 [15], APC [16,17], forkhead box (FoxO) proteins [18,19], and topoisomerase I/II [20].”
IKKα aggravates renal fibrogenesis by positively regulating the Wnt/β‐catenin pathway
Zhang, H., Pan, B., Huang, W., Ma, M., Zhang, F., Jiang, L., Cheng, Q., Wan, X. H., & Cao, C. (2022) · Immunology · doi:10.1111/imm.13567 · Cited by 10
“Multiple factors including Wnt signalling, APC [51] regulate the cellular localization of β-catenin.”
BackgroundInfluential
Shifting the Focus of Signaling Abnormalities in Colon Cancer
Brown, M. A., & Ried, T. (2022) · Cancers · doi:10.3390/cancers14030784 · Cited by 11
Nucleocytoplasmic transport of huntingtin and Huntington's disease
Truant, R. (2003) · Clinical Neuroscience Research · doi:10.1016/s1566-2772(03)00058-6 · Cited by 10
Chasing chaos
Kelsey, J., Timmis, J., & Hone, A. N. W. (2003) · IEEE Congress on Evolutionary Computation (CEC) · doi:10.1109/cec.2003.1299605 · Cited by 10
BCAP31 is involved in modulating colorectal cancer cell proliferation via the Emerin/β-catenin axis
Han, L., Shi, J., Zhao, L., Deng, J., Li, Y., Zhao, H., Wang, H., Yan, Y., & Zou, F. (2022) · Experimental Cell Research · doi:10.1016/j.yexcr.2022.113265 · Cited by 9
Dynamic properties of APC‐decorated microtubules in living cells
Dayanandan, R., Butler, R., Gordon‐Weeks, P. R., Matus, A. I., Kaech, S., Lovestone, S., Anderton, B. H., & Gallo, J. (2003) · Cell Motility and the Cytoskeleton · doi:10.1002/cm.10096 · Cited by 9
Evidence for the Nucleo-Apical Shuttling of a Beta-Catenin Like Plasmodium falciparum Armadillo Repeat Containing Protein
Mitra, P., Gupta, E. D., Sahar, T., Pandey, A. K., Dangi, P., Reddy, K. S., Chauhan, V. S., & Gaur, D. (2016) · PLoS ONE · doi:10.1371/journal.pone.0148446 · Cited by 8
“EMSA showing DNA binding activity of PfARO was performed as described earlier [29, 36].”
Method
β‐Catenin can bind directly to CRM1 independently of adenomatous polyposis coli, which affects its nuclear localization and LEF‐1/β‐catenin‐dependent gene expression
Ki, H., Oh, M., Chung, S. W., & Kim, K. (2008) · Cell Biology International · doi:10.1016/j.cellbi.2007.12.008 · Cited by 8
“Indeed, all components of the complex required for b-catenin degradation, including GSK 3b, Axin, and APC, have been shown to enter the nucleus (Rosin-Arbesfeld et al., 2000; Henderson, 2000; Wiechens et al., 2004; Neufeld et al., 2000a).”
Background
Fibersol-2 induces apoptosis ofApc-deficient colorectal Cancer (SW480) cells and decreases polyp formation inApcMIN mice
Cuesta‐Sancho, S., Olson, S. L., So, E. Y., Shimomura, K., Ouchi, T., & Preuss, F. (2016) · Cancer Biology & Therapy · doi:10.1080/15384047.2016.1177685 · Cited by 8
Armadillo takes the APC shuttle
Clevers, H. C. (2000) · Nature Cell Biology · doi:10.1038/35036424 · Cited by 8
Overexpressed LEF‐1 proteins display different nuclear localization patterns of β‐catenin in normal versus tumor cells
Ki, H., Jung, H., Park, J. H., Kim, J., Lee, K. Y., Kim, T. S., & Kim, K. (2005) · Cell Biology International · doi:10.1016/j.cellbi.2005.11.005 · Cited by 7
“It is of great interest to note that APC, one of the b-catenin binding proteins, also has a nuclear export function (Henderson, 2000; Rosin-Arbesfeld et al., 2000, 2003).”
Background
Tumor Suppressors APC and VHL: Gatekeepers of the Intestine and Kidney
Giles, R. H., & Voest, E. E. (2005) · Springer eBooks · doi:10.1007/3-540-27671-8_7 · Cited by 6
“struction machinery (Henderson 2000; Neufeld et al. 2000; Rosin-Arbesfeld et al. 2000).”
Background
Multiple roles of Adenomatous Polyposis Coli gene in Wnt Signalling – a Computational Model
Raji, R. J., Sasikumar, R., & Jacob, E. (2018) · Biosystems · doi:10.1016/j.biosystems.2018.08.001 · Cited by 7
Catenin, beta
Takemaru, K. (2006) · AfCS-Nature Molecule Pages · doi:10.1038/mp.a000506.01 · Cited by 6
Fusion of the BCL9 HD2 domain to E1A increases the cytopathic effect of an oncolytic adenovirus that targets colon cancer cells
Fuerer, C., Homicskó, K., Lukashev, A. N., Pittet, A.-L., & Iggo, R. D. (2006) · BMC Cancer · doi:10.1186/1471-2407-6-236 · Cited by 5
“APC has been shown to mediate export of β-catenin through clusters of nuclear export signals (NES) at the N-terminus and in the central region preceding the axin binding site [31,32].”
Background
The APC Tumor Suppressor Pathway
Morin, P. J., & Weeraratna, A. T. (2003) · Humana Press eBooks · doi:10.1385/1-59259-328-3:021 · Cited by 6
“At its N terminus, APC also contains two nuclear export sequences at amino acids 68–77 and 165–174, as well as a putative one at 1472–1481 (80).”
Background
TRANSCRIPTION FACTORS AND HUMAN DISEASE
Latchman, D. S. (2008) · Elsevier eBooks · doi:10.1016/b978-012373983-4.50017-1 · Cited by 7
APC 3×15 β-catenin-binding domain potentiates β-catenin association to TBP and upregulates TCF-4 transcriptional activity
Roura, S., Martı́nez, D., Piedra, J. A., Miravet, S., de Herreros, A. G., & Duñach, M. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.08.075 · Cited by 5
C. elegans Genetic Networks Predict Roles for O-GlcNAc Cycling in Key Signaling Pathways
Mondoux, M. A., Krause, M., & Hanover, J. A. (2010) · Current Signal Transduction Therapy · doi:10.2174/157436210790226456 · Cited by 5
“Modification by O-GlcNAc regulates the binding of β-catenin to its nuclear binding partner TCF4, but not to the APC tumor suppressor protein [61], which functions in the nuclear export of β-catenin [62, 63].”
Direct metabolic regulation of β-catenin activity by the p85α regulatory subunit of phosphoinositide 3-OH kinase
Espada, J., Peinado, H., Esteller, M., & Cano, A. (2005) · Experimental Cell Research · doi:10.1016/j.yexcr.2005.01.009 · Cited by 5
Inter- and Supramolecular Interactions of Protein Kinase CK2 and their Relevance for Genome Integrity
Olsen, B. B., Niefind, K., & Issinger, O. (2006) · Springer eBooks · doi:10.1007/7050_002 · Cited by 5
“APC also exports β-catenin from the nucleus (Henderson 2000; Rosin-Arbesfeld et al. 2000).”
Background
A yeast model system for functional analysis of β-catenin signaling
Lee, M. S., D'Amour, K. A., & Papkoff, J. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200204063 · Cited by 5
“This hypothesis is further supported by studies suggesting that -cat is exported from the nucleus by APC in a manner dependent upon the CRM-1 export receptor (Henderson, 2000; Rosin-Arbesfeld et al., 2000).”
BackgroundInfluential
Nonsteroidal Anti-Inflammatory Drugs, Prostaglandins, and Apc-Driven Intestinal Tumorigenesis
Whelan, J., & McEntee, M. F. (2003) · Humana Press eBooks · doi:10.1007/978-1-59259-302-6_8 · Cited by 5
Wnt Signal Transduction
Ilyas, M. (2007) · Wiley eBooks · doi:10.1002/9780470025079.chap14.pub2 · Cited by 6
The Wnt/β-catenin-P2-HNF4α feedback loop facilitates colorectal tumorigenesis and malignancy
Bai, W., Dong, R., Lu, C., Sang, L., Hao, Q., Zhang, Y., Sun, R., Shen, J., Zhu, W., Sun, Y., et al. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07133-7 · Cited by 4
“While key oncogenic drivers in CRC development have been identified, including Ras [3], TP53 [4], and APC/β-catenin [5], the common pathogenesis remains elusive.”
Identifying novel interactions of the colon-cancer related APC protein with Wnt-pathway nuclear transcription factors
Al‐Thani, N. M., Schaefer‐Ramadan, S., Aleksic, J., Mohamoud, Y. A., & Malek, J. A. (2022) · Cancer Cell International · doi:10.1186/s12935-022-02799-1 · Cited by 4
“A) In the absence of Wnt, the destruction complex (APC, AXIN, CK1α, and GSK3β) binds and phosphorylates CTNNB1 to mark it for proteasomal degradation.”
BackgroundInfluential
Wnt Signaling Networks and Embryonic Patterning
Klymkowsky, M. W. (2007) · Springer eBooks · doi:10.1007/0-387-28671-3_18 · Cited by 4
Postgenomic technologies targeting the Wnt signaling network
Pancratov, R., & DasGupta, R. (2011) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.140 · Cited by 3
Wnt/β-Catenin Signaling and Oral Cancer Metastasis
Zhou, G. (2009) · Springer eBooks · doi:10.1007/978-1-4419-0775-2_11 · Cited by 4
“The APC protein has been shown to have a nuclear export function for b-catenin (Neufeld et al. 2000; Rosin-Arbesfeld et al. 2000).”
Background
Wnt/β-catenin signaling pathway and its role in hepatocellular carcinoma
Zhang, X., Yu, L., & Lu, Y. (2008) · Frontiers of Medicine · doi:10.1007/s11684-008-0042-x · Cited by 3
A Framework for modelling stochastic optimisation algorithms with Markov chains
Clark, E. B. (2008) · Cited by 3
Cell Polarity and Asymmetric Cell Division by the Wnt Morphogen
Baldwin, A. T., & Phillips, B. T. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-802438-6.00003-6 · Cited by 3
Transcription Factors and Human Disease
Latchman, D. S. (2004) · Elsevier eBooks · doi:10.1016/b978-012437178-1/50015-1 · Cited by 3

Authors: Rosin-Arbesfeld, R., Townsley, F., & Bienz, M.
Affiliations: MRC Laboratory of Molecular Biology (GB)
Corresponding author: Bienz, Mariann
ORCID: Bienz, Mariann
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2000-08
Volume: 406
Issue: 6799
Pages: 1009-1012
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/35023016
OpenAlex: W1666932156
Cited by: 343
References: 30
Citations by year: 2026: 2 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 7 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 8 · 2017: 4 · 2016: 6 · 2015: 6 · 2014: 7 · 2013: 12 · 2012: 10
FWCI: 15.18
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords: nuclear export, nuclear export signal, β-catenin stabilization, colorectal cancer, proteasomal degradation, armadillos, mutation cluster region, tumor suppressor function
MeSH terms: Amino Acid Sequence, Animals, Biological Transport, Cell Nucleus, Cytoskeletal Proteins, Drosophila, Fatty Acids, Unsaturated, Multigene Family, Genetic Complementation Test, Humans, Molecular Sequence Data, Mutation, Peptide Fragments, Recombinant Fusion Proteins, Transfection, Tumor Cells, Cultured, Colorectal Neoplasms, Trans-Activators, Conserved Sequence, Genes, Reporter, COS Cells, Adenomatous Polyposis Coli Protein, beta Catenin

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The APC tumour suppressor has a nuclear export function

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