Atonal homolog 1 is required for growth and differentiation effects of notch/gamma-secretase inhibitors on normal and cancerous intestinal epithelial cells.

Gastroenterology
Avedis KazanjianNoah Shroyer

Abstract

The atonal homolog 1 (Atoh1) transcription factor is required for intestinal secretory (goblet, Paneth, enteroendocrine) cell differentiation. Notch/gamma-secretase inhibitors (GSIs) block proliferation and induce secretory cell differentiation in the intestine. We used genetic analyses of mice to determine whether Atoh1 mediates the effects of GSIs in normal and cancerous intestinal epithelia. We studied mice with intestine-specific disruption of Atoh1 (Atoh1(Deltaintestine)), the adenomatosis polyposis coli (APC)(min) mutation, both mutations (Atoh1(Deltaintestine); APC(min)), or littermate controls; mice were given GSI or vehicle. Colorectal cancer (CRC) cell lines were treated with GSI or vehicle and with small hairpin RNAs to reduce ATOH1. Differentiation and homeostasis were assessed by protein, RNA, and histologic analyses. GSIs failed to induce secretory cell differentiation or apoptosis or decrease proliferation of Atoh1-null progenitor cells, compared with wild-type cells. Exposure of APC(min) adenomas to GSIs decreased proliferation and increased secretory cell numbers in an Atoh1-dependent manner. In CRC cells treated with GSI, ATOH1 levels were correlated inversely with proliferation. ATOH1 was required for secreto...Continue Reading

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Citations

Mar 1, 2012·Journal of the Association for Research in Otolaryngology : JARO·Joanna Mulvaney, Alain Dabdoub
Oct 11, 2011·Digestive Diseases and Sciences·Hao ChenXiaoxin Chen
Feb 23, 2012·Proceedings of the National Academy of Sciences of the United States of America·Tae-Hee KimRamesh A Shivdasani
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Mar 16, 2011·The Journal of Experimental Medicine·Tae-Hee Kim, Ramesh A Shivdasani
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Feb 5, 2013·Gastroenterology·Taeko K NoahNoah F Shroyer
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