Basic–alimentary tractp27kip1 Regulates cdk2 Activity in the Proliferating Zone of the Mouse Intestinal Epithelium: Potential Role in Neoplasia
Section snippets
Mice
Mice with functional inactivation of both p27 alleles (p27Δ51/Δ51) because of disruption of the N-terminal cdk inhibitory domain (giving an approximately 20-kilodalton truncated p27 protein, Δ51, unable to bind to cdk2 and cdk4) have been described previously.18 p21−/− mice have been described previously.24 Mice were maintained on AIN-76 diet from Harlan-Teklad (Madison, WI) from weaning at approximately 3 weeks after birth until death at 13 to 14 weeks of age (prior to onset of tumor-related
Results
We first used a biochemical approach to determine expression and activity of G1/S-regulatory proteins along the normal murine small intestinal crypt-villus axis. Cells were fractionated according to their position along the crypt-villus axis using a method we have extensively validated,23 and the fractionation procedure was monitored in each experiment by determining expression of PCNA (a marker of proliferative crypt epithelial cells) and villin (a marker of differentiated villus cells) (
Discussion
Although cells undergo rapid proliferation in the small intestinal crypt, it is likely that, in the normal crypt, this is regulated. Here, we showed that the cdk inhibitor p27 is uniquely localized to the proliferative crypt compartment. Moreover, using a mouse with a targeted inactivation of p27, we showed that p27 significantly limits the extent of cdk2 activity in the crypt, and we propose that this regulates cell cycle progression within the proliferative compartment. Unlike p21, p57, and
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2009, Journal of Biological ChemistryCitation Excerpt :Contradictory results have been reported by using different methods to localize cell cycle regulatory protein expression in the small intestine. For example, p27 is a cell cycle inhibitor of the Cip/Kip family and its expression was found to be highest in proliferating crypt cells (35). However, in another report, p27 expression was found to be exclusively in the villi, and its expression in crypts was repressed by Notch signaling to maintain proliferating crypt progenitor cells (36).
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2008, Experimental Cell ResearchIntestinal Deletion of Pofut1 in the Mouse Inactivates Notch Signaling and Causes Enterocolitis
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The authors have no conflict of interest to disclose.
Supported in part by NCI grants RO1 CA114265 and U54 CA100926.