Dataset Information

Functional comparison of human adenomatous polyposis coli (APC) and APC-like in targeting beta-catenin for degradation.

ABSTRACT: Truncating mutations affect the adenomatous polyposis coli (APC) gene in most cases of colon cancer, resulting in the stabilization of ?-catenin and uncontrolled cell proliferation. We show here that colon cancer cell lines express also the paralog APC-like (APCL or APC2). RNA interference revealed that it controls the level and/or the activity of ?-catenin, but it is less efficient and binds less well to ?-catenin than APC, thereby providing one explanation as to why the gene is not mutated in colon cancer. A further comparison indicates that APCL down-regulates the ?-catenin level despite the lack of the 15R region known to be important in APC. To understand this discrepancy, we performed immunoprecipitation experiments that revealed that phosphorylated ?-catenin displays a preference for binding to the 15 amino acid repeats (15R) rather than the first 20 amino acid repeat of APC. This suggests that the 15R region constitutes a gate connecting the steps of ?-catenin phosphorylation and subsequent ubiquitination/degradation. Using RNA interference and domain swapping experiments, we show that APCL benefits from the 15R of truncated APC to target ?-catenin for degradation, in a process likely involving heterodimerization of the two partners. Our data suggest that the functional complementation of APCL by APC constitutes a substantial facet of tumour development, because the truncating mutations of APC in colorectal tumours from familial adenomatous polyposis (FAP) patients are almost always selected for the retention of at least one 15R.

SUBMITTER: Schneikert J

PROVIDER: S-EPMC3698177 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Functional comparison of human adenomatous polyposis coli (APC) and APC-like in targeting beta-catenin for degradation.

Schneikert Jean J Vijaya Chandra Shree Harsha SH Ruppert Jan Gustav JG Ray Suparna S Wenzel Eva Maria EM Behrens Jürgen J

PloS one 20130701 7

Truncating mutations affect the adenomatous polyposis coli (APC) gene in most cases of colon cancer, resulting in the stabilization of β-catenin and uncontrolled cell proliferation. We show here that colon cancer cell lines express also the paralog APC-like (APCL or APC2). RNA interference revealed that it controls the level and/or the activity of β-catenin, but it is less efficient and binds less well to β-catenin than APC, thereby providing one explanation as to why the gene is not mutated in ...[more]

PMID: 23840886

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Project description:BackgroundMelanoma-intrinsic activated β-catenin pathway, the product of the catenin beta 1 (CTNNB1) gene, has been associated with low/absent tumor-infiltrating lymphocytes, accelerated tumor growth, metastases development, and resistance to anti-PD-L1/anti-CTLA-4 agents in mouse melanoma models. Little is known about the association between the adenomatous polyposis coli (APC) and CTNNB1 gene mutations in stage IV melanoma with immunotherapy response and overall survival (OS).MethodsWe examined the prognostic significance of somatic APC/CTNNB1 mutations in the Cancer Genome Atlas Project for Skin Cutaneous Melanoma (TCGA-SKCM) database. We assessed APC/CTNNB1 mutations as predictors of response to immunotherapies in a clinicopathologically annotated metastatic patient cohort from three US melanoma centers.ResultsIn the TCGA-SKCM patient cohort (n = 434) presence of a somatic APC/CTNNB1 mutation was associated with a worse outcome only in stage IV melanoma (n = 82, median OS of APC/CTNNB1 mutants vs. wild-type was 8.15 vs. 22.8 months; log-rank hazard ratio 4.20, p = 0.011). APC/CTNNB1 mutation did not significantly affect lymphocyte distribution and density. In the 3-melanoma institution cohort, tumor tissues underwent targeted panel sequencing using two standards of care assays. We identified 55 patients with stage IV melanoma and APC/CTNNB1 genetic aberrations (mut) and 169 patients without (wt). At a median follow-up of more than 25 months for both groups, mut compared with wt patients had slightly more frequent (44% vs. 39%) and earlier (66% vs. 45% within six months from original diagnosis of stage IV melanoma) development of brain metastases. Nevertheless, time-to-development of brain metastases was not significantly different between the two groups. Fortunately, mut patients had similar clinical benefits from PD-1 inhibitor-based treatments compared to wt patients (median OS 26.1 months vs. 29.9 months, respectively, log-rank p = 0.23). Less frequent mutations in the NF1, RAC1, and PTEN genes were seen in the mut compared with wt patients from the 3-melanoma institution cohort. Analysis of brain melanoma tumor tissues from a separate craniotomy patient cohort (n = 55) showed that melanoma-specific, activated β-catenin (i.e., nuclear localization) was infrequent (n = 3, 6%) and not prognostic in established brain metastases.ConclusionsAPC/CTNNB1 mutations are associated with a worse outcome in stage IV melanoma and early brain metastases independent of tumor-infiltrating lymphocyte density. However, PD1 inhibitor-based treatments provide comparable benefits to both mut and wt patients with stage IV melanoma.

Dataset Information

Functional comparison of human adenomatous polyposis coli (APC) and APC-like in targeting beta-catenin for degradation.

Publications

Functional comparison of human adenomatous polyposis coli (APC) and APC-like in targeting beta-catenin for degradation.

Similar Datasets

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