Up-regulation of CYP26A1 in Adenomatous Polyposis Coli–Deficient Vertebrates via a WNT-Dependent Mechanism: Implications for Intestinal Cell Differentiation and Colon Tumor Development

Elucidating signaling pathways that regulate cellular metabolism is essential for a better understanding of normal development and tumorigenesis. Recent studies have shown that mitochondrial pyruvate carrier 1 (MPC1), a crucial player in pyruvate metabolism, is downregulated in colon adenocarcinomas. Utilizing zebrafish to examine the genetic relationship between MPC1 and Adenomatous polyposis coli (APC), a key tumor suppressor in colorectal cancer, we found that apc controls the levels of mpc1 and that knock down of mpc1 recapitulates phenotypes of impaired apc function including failed intestinal differentiation. Exogenous human MPC1 RNA rescued failed intestinal differentiation in zebrafish models of apc deficiency. Our data demonstrate a novel role for apc in pyruvate metabolism and that pyruvate metabolism dictates intestinal cell fate and differentiation decisions downstream of apc.

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Adenomatous Polyposis Coli and Hypoxia-inducible Factor-1α Have an Antagonistic Connection

Molecular Biology of the Cell ◽

10.1091/mbc.e10-04-0312 ◽

2010 ◽

Vol 21 (21) ◽

pp. 3630-3638 ◽

Cited By ~ 28

Author(s):

Ian P. Newton ◽

Niall S. Kenneth ◽

Paul L. Appleton ◽

Inke Näthke ◽

Sonia Rocha

Keyword(s):

Adenomatous Polyposis Coli ◽

Hypoxia Inducible Factor ◽

Nuclear Factor Κb ◽

Survival Advantage ◽

Adenomatous Polyposis ◽

Polyposis Coli ◽

Hypoxic Conditions ◽

Low Levels ◽

Responsive Element ◽

Dependent Mechanism

The tumor suppressor adenomatous polyposis coli (APC) is mutated in the majority of colorectal cancers and is best known for its role as a scaffold in a Wnt-regulated protein complex that determines the availability of β-catenin. Another common feature of solid tumors is the presence of hypoxia as indicated by the up-regulation of hypoxia-inducible factors (HIFs) such as HIF-1α. Here, we demonstrate a novel link between APC and hypoxia and show that APC and HIF-1α antagonize each other. Hypoxia results in reduced levels of APC mRNA and protein via a HIF-1α–dependent mechanism. HIF-1α represses the APC gene via a functional hypoxia-responsive element on the APC promoter. In contrast, APC-mediated repression of HIF-1α requires wild-type APC, low levels of β-catenin, and nuclear factor-κB activity. These results reveal down-regulation of APC as a new mechanism that contributes to the survival advantage induced by hypoxia and also show that loss of APC mutations produces a survival advantage by mimicking hypoxic conditions.

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Loss of TRAIL-R does not affect thymic or intestinal tumor development in p53 and adenomatous polyposis coli mutant mice

Cell Death and Differentiation ◽

10.1038/sj.cdd.4401523 ◽

2004 ◽

Vol 12 (1) ◽

pp. 94-97 ◽

Cited By ~ 32

Author(s):

H H Yue ◽

G E Diehl ◽

A Winoto

Keyword(s):

Adenomatous Polyposis Coli ◽

Tumor Development ◽

Mutant Mice ◽

Intestinal Tumor ◽

Adenomatous Polyposis ◽

Polyposis Coli ◽

Coli Mutant

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Abstract 3671: Polarity and tumor development: Regulation by adenomatous polyposis coli

10.1158/1538-7445.am2016-3671 ◽

2016 ◽

Author(s):

Alyssa C. Lesko ◽

Madeline Chandra ◽

Jenifer R. Prosperi

Keyword(s):

Adenomatous Polyposis Coli ◽

Tumor Development ◽

Adenomatous Polyposis ◽

Polyposis Coli ◽

Development Regulation

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Adenomatous polyposis coli protein (APC)-independent regulation of β-catenin/Tcf-4 mediated transcription in intestinal cells

Biochemical Journal ◽

10.1042/bj3440565 ◽

1999 ◽

Vol 344 (2) ◽

pp. 565-570 ◽

Cited By ~ 8

Author(s):

Josep BAULIDA ◽

Eduard BATLLE ◽

Antonio GARCÍA DE HERREROS

Keyword(s):

Adenomatous Polyposis Coli ◽

Transcriptional Activity ◽

Intestinal Cell ◽

Adenomatous Polyposis ◽

Polyposis Coli ◽

Binding Assays ◽

Adenomatous Polyposis Coli Protein ◽

Kinase C ◽

Intestinal Cell Lines

Alterations in the transcriptional activity of the β-catenin-Tcf complex have been associated with the earlier stages of colonic transformation. We show here that the activation of protein kinase C by the phorbol ester PMA in several intestinal cell lines increases the levels of β-catenin detected in the nucleus and augments the transcriptional activity mediated by β-catenin. The response to PMA was not related to modifications in the cytosolic levels of β-catenin and was observed not only in cells with wild-type adenomatous polyposis coli protein (APC) but also in APC-deficient cells. Binding assays in vitro revealed that PMA facilitates the interaction of the β-catenin with the nuclear structure. Our results therefore show that β-catenin-mediated transcription can be regulated independently of the presence of APC.

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