The APC Tumor Suppressor Inhibits DNA Replication by Directly Binding to DNA via Its Carboxyl Terminus

Jiang, Qian; Sarnaik, Amod A.; Bonney, Tera; Keirsey, Jeremy; Combs, Kelly A.; Steigerwald, Kira; Acharya, Samir; Behbehani, Gregory K.; Barton, Michelle C.; Lowy, Andrew M.; Groden, Joanna

doi:10.1053/j.gastro.2008.03.074

Cited by 35 publications

(29 citation statements)

References 39 publications

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“…2), and that this interaction was diminished for a truncated mutant form of APC. Complementary to these studies that analyzed cellular changes caused by modulation of endogenous APC, the ectopic expression of a carboxyl terminal fragment (aa 2140-2421) of APC was shown to cause inhibition of DNA replication in assays using Xenopus laevis egg extracts (26). The repression was proposed to involve direct DNA binding by APC.…”

Section: Apc In the Nucleus: Regulating Dna Replication And Repairmentioning

confidence: 97%

APC as a mobile scaffold: Regulation and function at the nucleus, centrosomes, and mitochondria

et al. 2011

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SummaryGenetic mutations of adenomatous polyposis coli (APC) predispose to high risk of human colon cancer. APC is a large tumor suppressor protein and truncating mutations disrupt its normal roles in regulating cell migration, DNA replication/ repair, mitosis, apoptosis, and turnover of oncogenic b-catenin. APC is targeted to multiple subcellular sites, and here we discuss recent evidence implicating novel protein interactions and functions of APC in the nucleus and at centrosomes and mitochondria. The ability of APC to shuttle between these and other cell locations is hypothesized to be integral to its cellular function. IUBMBIUBMB Life, 64(3): 209-214, 2012

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Section: Apc In the Nucleus: Regulating Dna Replication And Repairmentioning

confidence: 97%

APC as a mobile scaffold: Regulation and function at the nucleus, centrosomes, and mitochondria

et al. 2011

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“…The physical interaction of APC with other proteins such as DLG may also be involved, as the C-terminal DLG-binding residues within APC are required for complete inhibition of S-phase entry in a mouse fibroblast cell model, while DLG overexpression in itself is sufficient to arrest cells at the G1/S transition [78]. The interaction of the APC C-terminus with A/T-rich DNA also blocks entry into or progression through S-phase by blocking DNA replication [79, 80]. These findings are consistent with evidence that defective G1/S-phase progression due to APC overexpression is only partially alleviated by co-transfection of a constitutively active mutant β-catenin [77].…”

Section: Apc Controls Dna Replication and Cell Cycle Progressionmentioning

confidence: 99%

Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting

Hankey

Frankel

Groden

2018

Cancer Metastasis Rev

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143

110

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The acquisition of biallelic mutations in the APC gene is a rate-limiting step in the development of most colorectal cancers and occurs in the earliest lesions. APC encodes a 312-kDa protein that localizes to multiple subcellular compartments and performs diverse functions. APC participates in a cytoplasmic complex that promotes the destruction of the transcriptional licensing factor β-catenin; APC mutations that abolish this function trigger constitutive activation of the canonical WNT signaling pathway, a characteristic found in almost all colorectal cancers. By negatively regulating canonical WNT signaling, APC counteracts proliferation, promotes differentiation, facilitates apoptosis and suppresses invasion and tumor progression. APC further antagonizes canonical WNT signaling by interacting with and counteracting β-catenin in the nucleus. APC also suppresses tumor initiation and progression in the colorectal epithelium through functions that are independent of canonical WNT signaling. APC regulates the mitotic spindle to facilitate proper chromosome segregation, localizes to the cell periphery and cell protrusions to establish cell polarity and appropriate directional migration, and inhibits DNA replication by interacting directly with DNA. Mutations in APC are often frameshifts, insertions or deletions that introduce premature stop codons and lead to the production of truncated APC proteins that lack its normal functions and possess tumorigenic properties. Therapeutic approaches in development for the treatment of APC-deficient tumors are focused on the inhibition of canonical WNT signaling, especially through targets downstream of APC in the pathway, or on the restoration of wild-type APC expression.

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“…To confirm that miR-135b overexpression is due to APC loss, we re-induced APC by transfecting a plasmid encoding the APC full coding sequence (CDS) in the SW480 human CRC cells, which only contains a mutated APC allele leading to a truncated protein (Qian et al, 2008) . Re-expression of wildtype (WT) APC caused a 65% reduction in miR-135b expression (p = 0.03), whereas inhibition of APC by siRNA resulted in a 5-fold increase (p = 0.01) in miR-135b expression in normal colon epithelial cell lines (Moyer et al, 1996;Figures 2A, 2B, and S2A-S2C) Inactivating mutations in APC cause stabilization and nuclear translocation of b-catenin with induction of a complex transcriptional program.…”

Section: Mir-135b Overexpression Is Associated With Mutations In Specmentioning

confidence: 99%

“…Both experiments resulted in increased miR-135b expression (3-fold [p = 0.003] and 4.6-fold [p = 0.007], respectively; Figures 2C and S2D). An siRNA screen against the major transcription factors involved in the APC/b-catenin axis was run on two cell lines with high basal b-catenin activity, HCT-116 (b-catenin mutant;Ilyas et al, 1997) and SW480 (APC null cells; Qian et al, 2008), revealing that TCF4 and LEF1 silencing causes miR-135b Cancer Cell miR-135b as a Therapeutic Target in Colon Cancer inhibition ( Figures 2D and S2E) . Taken together, these data suggest that miR-135b can be activated by the APC/b-catenin/ TCF4-LEF1 pathway.…”

Section: Mir-135b Overexpression Is Associated With Mutations In Specmentioning

confidence: 99%

microRNA-135b promotes cancer progression acting as a downstream effector of oncogenic pathways in colon cancer

Valeri¹,

Braconi²,

Gasparini³

et al. 2013

The Lancet

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SUMMARYMicroRNA deregulation is frequent in human colorectal cancers (CRCs), but little is known as to whether it represents a bystander event or actually drives tumor progression in vivo. We show that miR-135b overexpression is triggered in mice and humans by APC loss, PTEN/PI3K pathway deregulation, and SRC overexpression and promotes tumor transformation and progression. We show that miR-135b upregulation is common in sporadic and inflammatory bowel disease-associated human CRCs and correlates with tumor stage and poor clinical outcome. Inhibition of miR-135b in CRC mouse models reduces tumor growth by controlling genes involved in proliferation, invasion, and apoptosis. We identify miR-135b as a key downsteam effector of oncogenic pathways and a potential target for CRC treatment.

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The APC Tumor Suppressor Inhibits DNA Replication by Directly Binding to DNA via Its Carboxyl Terminus

Cited by 35 publications

References 39 publications

APC as a mobile scaffold: Regulation and function at the nucleus, centrosomes, and mitochondria

APC as a mobile scaffold: Regulation and function at the nucleus, centrosomes, and mitochondria

Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting

microRNA-135b promotes cancer progression acting as a downstream effector of oncogenic pathways in colon cancer

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