Altered dynamics of intestinal cell maturation in APC1638N/+ mice

Donghai Wang, Rossanna C. Pezo, Georgia Corner, Cristina Sison, Martin L. Lesser, Shailesh M. Shenoy, John M. Mariadason, Robert H. Singer, Leonard H. Augenlicht

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 Apc1638N/+ 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 Hif1α and its target genes. Thus, although intestinal tumors develop in Apc1638N/+ 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.

Original languageEnglish (US)
Pages (from-to)5348-5357
Number of pages10
JournalCancer Research
Volume70
Issue number13
DOIs
StatePublished - Jul 1 2010

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Genes
Alleles
myc Genes
Citric Acid Cycle
Interphase
Gene Expression Profiling
Intestinal Mucosa
Energy Metabolism
Transcriptional Activation
Intestines
Catalytic Domain
Neoplasms
Homeostasis
Down-Regulation
Epithelial Cells
Enzymes
Cellular Reprogramming

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Altered dynamics of intestinal cell maturation in APC1638N/+ mice. / Wang, Donghai; Pezo, Rossanna C.; Corner, Georgia; Sison, Cristina; Lesser, Martin L.; Shenoy, Shailesh M.; Mariadason, John M.; Singer, Robert H.; Augenlicht, Leonard H.

In: Cancer Research, Vol. 70, No. 13, 01.07.2010, p. 5348-5357.

Research output: Contribution to journalArticle

Wang, D, Pezo, RC, Corner, G, Sison, C, Lesser, ML, Shenoy, SM, Mariadason, JM, Singer, RH & Augenlicht, LH 2010, 'Altered dynamics of intestinal cell maturation in APC1638N/+ mice', Cancer Research, vol. 70, no. 13, pp. 5348-5357. https://doi.org/10.1158/0008-5472.CAN-09-4593
Wang, Donghai ; Pezo, Rossanna C. ; Corner, Georgia ; Sison, Cristina ; Lesser, Martin L. ; Shenoy, Shailesh M. ; Mariadason, John M. ; Singer, Robert H. ; Augenlicht, Leonard H. / Altered dynamics of intestinal cell maturation in APC1638N/+ mice. In: Cancer Research. 2010 ; Vol. 70, No. 13. pp. 5348-5357.
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