Opposing roles for p21(waf1/cip1) and p27(kip1) in enterocyte differentiation, proliferation, and migration.
BACKGROUND
Originating from proliferating stem cells of the intestinal crypt, enterocytes differentiate as they migrate up the crypt-villus axis. A regulatory role of the cyclin-dependent kinase inhibitors p21(waf1/cip1) and p27(kip1) in these processes has been suggested by in vitro models. We sought to determine the effect of p21(waf1/cip1) and p27(kip1) deficiency on enterocyte differentiation, proliferation and migration.


METHODS
Three strains of mice including control (C57Bl/6), p27(kip1)-null, and p21(waf1/cip1)-null were studied. Enterocyte differentiation was evaluated by immunostaining for intestinal alkaline phosphatase, by colorimetric assaying for intestinal alkaline phosphatase and sucrase enzyme activity, and by polymerase chain reaction for intestinal fatty acid-binding protein and villin-messenger RNA in enterocytes extracted by laser capture microdissection. Rates of enterocyte proliferation and migration were determined by 5-bromo 2-deoxyuridine immunostaining after a 50% small-bowel resection (SBR).


RESULTS
Compared with controls, p27(kip1)-null mice demonstrated minimal differentiation but maintained a normal proliferative response to SBR. Contrarily, p21(waf1/cip1)-null mice demonstrated greater enterocyte differentiation without significant increases in enterocyte proliferation after SBR.


CONCLUSIONS
These findings suggest that p21(waf1/cip1) and p27(kip1) have distinctive and opposing roles in the pathogenesis of enterocyte differentiation, proliferation, and migration.
Stehr
Wolfgang
W
Division of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, OH 45229-3039, USA.
Mercer
Timothy I
TI
Bernal
Nicole P
NP
Erwin
Christopher R
CR
Warner
Brad W
BW
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020895:Enterocytes / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27