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

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2018

Erschienen:

2018

Enthalten in:

Zur Gesamtaufnahme - volume:37

Enthalten in:

Cancer metastasis reviews - 37(2018), 1 vom: 09. März, Seite 159-172

Sprache:

Englisch

Beteiligte Personen:

Hankey, William [VerfasserIn]
Frankel, Wendy L [VerfasserIn]
Groden, Joanna [VerfasserIn]

Links:

Volltext

Themen:

APC
APC protein, human
Adenomatous Polyposis Coli Protein
Biomarkers, Tumor
Canonical WNT signaling
Colorectal cancer
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Therapeutics
WNT-independent

Anmerkungen:

Date Completed 01.04.2019

Date Revised 03.01.2021

published: Print

Citation Status MEDLINE

doi:

10.1007/s10555-017-9725-6

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM279812868