Loss of p21 Waf1/Cip1/Sdl1 enhances intestinal stem cell survival following radiation injury

Robert J. George, Mark A. Sturmoski, Randal May, Sripathi M. Sureban, Brian K. Dieckgraefe, Shrikant Anant, Courtney W. Houchen

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

The microcolony assay following gamma irradiation (IR) is a functional assay of intestinal stem cell fate. The cyclin-dependent kinase (CDK) inhibitor p21 Waf1/Cip1/Sdi1 (p21) regulates cell cycle arrest following DNA damage. To explore the role of p21 on stem cell fate, we examined the effects of p21 deletion on intestinal crypt survival following IR and expression of the stem/progenitor cell marker Musashi-1 (Msi-1) and the antiapoptotic gene survivin. Intestinal stem cell survival in adult wild-type (WT) and p21 -/- mice was measured using the micro-colony assay. Msi-1, p21, and survivin mRNA were measured using real-time PCR and immunohistochemical analysis. Laser capture microdissection (LCM) was used to isolate mRNA from the crypt stem cell zone. No differences in radiation-induced apoptosis were observed between WT and p21 -/- mice. However, increased crypt survival (3.0-fold) was observed in p21 -/- compared with WT mice 3.5 days after 13 Gy. Msi-1 and survivin mRNA were elevated 12-and 7.5-fold, respectively, in LCM-dissected crypts of p21 -/- compared with WT mice. In conclusion, deletion of p21 results in protection of crypt stem/progenitor cells from IR-induced cell death. Furthermore, the increase in crypt survival is associated with increased numbers of Msi-1- and survivin-expressing cells in regenerative crypts.

Original languageEnglish
Pages (from-to)G245-G254
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume296
Issue number2
DOIs
StatePublished - Feb 2009

Keywords

  • Crypt survival
  • Gamma irradiation
  • Musashi-1
  • Survivin

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