当前位置： SCI文献检索 > ONCOGENE期刊下所有文献 > Apc and p53 interaction in DNA damage and genomic instability in hepatocytes.

Apc and p53 interaction in DNA damage and genomic instability in hepatocytes.

Abstract：

:Disruption of Apc (adenomatous polyposis coli) within hepatocytes activates Wnt signalling, perturbs differentiation and ultimately leads to neoplasia. Apc negatively regulates Wnt signalling but is also involved in organizing the cytoskeleton and may have a role in chromosome segregation. In vitro studies have implicated Apc in the control of genomic stability. However, the relevance of this data has been questioned in vivo as Apc is lost earlier than the onset of genomic instability. Here we analyse the relationship between immediate loss of Apc and the acquisition of genomic instability in hepatocytes. We used Cre-lox technology to inactivate Apc and in combination with p53 in vivo, to define the consequences of gene loss on cell cycle regulation, proliferation, death and aneuploidy. We show that, although Apc loss leads to increased proliferation, it also leads to increased apoptosis, the accumulation of p53, p21 and markers of double-strand breaks and DNA repair. Flow cytometry revealed an increased 4N DNA content, consistent with a G2 arrest. Levels of anaphase bridges were also elevated, implicating failed chromosome segregation. This was accompanied by an increase in centrosome number, which demonstrates a role for Apc in maintaining euploidy. To address the role of p53 in these processes, we analysed combined loss of Apc and p53, which led to a further increase in proliferation, cell death, DNA damages and repair and a bypass of G2 arrest than was observed with Apc loss. However, we observed only a marginal effect on anaphase bridges and centrosome number, which could be due to increased cell death. Our data therefore establishes, in an in vivo setting, that APC loss leads to a DNA damage signature and genomic instability in the liver and that additional loss of p53 leads to an increase in the DNA damage signal but not to an immediate increase in the genomic instability phenotype.

journal_name

Oncogene

journal_title

Oncogene

authors

Méniel V,Megges M,Young MA,Cole A,Sansom OJ,Clarke AR

doi

10.1038/onc.2014.342

subject

Has Abstract

pub_date

2015-07-30 00:00:00

pages

4118-29

issue

eissn

0950-9232

issn

1476-5594

pii

onc2014342

journal_volume

pub_type

杂志文章

在线工具

Apc and p53 interaction in DNA damage and genomic instability in hepatocytes.