Article thumbnail

Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors

By Johan H. van Es, Natalie de Geest, Maaike van de Born, Hans Clevers and Bassem A. Hassan

Abstract

Intestinal cells are constantly produced from a stem cell reservoir that gives rise to proliferating transient amplifying cells, which subsequently differentiate into one of the four principal cell types. Signalling pathways, including the Notch signalling pathway, coordinate these differentiation processes and their deregulation may cause cancer. Pharmacological inhibition through γ-secretase inhibitors or genetic inactivation of the Notch signalling pathway results in the complete loss of proliferating crypt progenitors due to their conversion into post-mitotic goblet cells. The basic helix–loop–helix transcription factor Math1 is essential for intestinal secretory cell differentiation. Because of the critical roles of both Math1 and Notch signalling in intestinal homeostasis and neoplastic transformation, we sought to determine the genetic hierarchy regulating the differentiation of intestinal stem cells into secretory cells. In this paper, we demonstrate that the conversion of intestinal stem cells into goblet cells upon inhibition of the Notch signalling pathway requires Math1

Topics: Article
Publisher: Nature Publishing Group
OAI identifier: oai:pubmedcentral.nih.gov:2895507
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2002). A . et al Colorectal cancer in mice genetically defi cient
  2. (2007). A . Intestinal homeostasis and neoplasia studied using conditional transgenesis .
  3. (2009). a r k e r
  4. B e r m i n g h a m , N . A . , F i n e g o l d ,
  5. (1999). e r m i n g h a m , N . A . et al. Math1: an essential gene for the generation of inner ear hair cells .
  6. (2007). h r o y e r
  7. I n t e r a c t i o n o f Muc2 and Apc on Wnt Signaling and in intestinal tumorigenesis: potential role of chronic infl ammation . Cancer Res.
  8. (2000). J e n s e n
  9. (1997). Math1 is essential for genesis of cerebellar granule neurons .
  10. (2005). Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease . Trends Mol.
  11. (2009). Notch signaling: the core pathway and its posttranslational r e g u l a t i o n .
  12. (2005). Notch signals control the fate of immature progenitor cells in the intestine .
  13. (2009). o s s u y t
  14. (2009). OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells .
  15. (2004). S a n s o m
  16. (2003). Targeted inactivation of p27 kip1 is suffi cient for large and small intestinal tumorigenesis in the mouse, which can be augmented by a Westernstyle high-risk diet . Cancer Res.
  17. Targeted inactivation of the p21 WAF1/cip1 gene enhances Apc -initiated tumor formation and the tumor-promoting activity of a Western-style high-risk diet by altering cell maturation in the intestinal mucosa . Cancer Res.
  18. (2009). Transcription factor achaete scute-like 2 controls intestinal stem cell fate .
  19. (2005). v a n E s