Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Cancer Res. 2010 Jul 1;70(13):5348-57. doi: 10.1158/0008-5472.CAN-09-4593. Epub 2010 Jun 22.

Altered dynamics of intestinal cell maturation in Apc1638N/+ mice.

Author information

  • 1Department of Medicine, Montefiore Medical Center, Bronx, New York 10467, USA.

Abstract

Novel imaging of active transcription sites in interphase nuclei of intestinal epithelial cells in situ showed that key genes associated with Wnt and Notch signaling were dynamically regulated as the cells underwent normal maturation during their migration along the mouse crypt-villus axis (CVA). However, oscillating patterns of activation of these genes were displaced along this axis in the histologically normal intestinal mucosa of Apc(1638N/+) mice before tumor development. Gene expression profiling then showed that the normal reprogramming of cells along the CVA was dampened in the Apc(1638N/+) mice, with an overrepresentation of c-myc target genes among those loci affected in the mutant mice. Moreover, in the Apc(1638N/+) mice, there was a perturbed pattern of expression of lineage-specific markers along the CVA consistent with transcription site repression of the Math1 gene, and genes encoding enzymes of every step of the tricarboxylic acid cycle were downregulated in the crypt of Apc(1638N/+) mice compared with WT, but not in the villus. These changes may alter energy metabolism and generate a pseudohypoxic state, suggested by elevated expression of Hif1alpha and its target genes. Thus, although intestinal tumors develop in Apc(1638N/+) mice on focal loss or inactivation of the WT allele, our results show that in the Apc(1638N/+) mouse, inheritance of only a single WT Apc allele perturbs the dynamic and complex reprogramming underlying normal cell maturation, which links epithelial function and homeostasis with architectural organization of the intestine.

Copyright 2010 AACR.

PMID:
20570902
[PubMed - indexed for MEDLINE]
PMCID:
PMC2906237
Free PMC Article

Images from this publication.See all images (5)Free text

Fig 1
Fig 2
Fig. 3
Fig 4
Fig 5
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk