, Volume 16, Issue 1, pp 148-155

Regulation of Retinoblastoma Protein (Rb) by p21 Is Critical for Adaptation to Massive Small Bowel Resection

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Abstract

Background

Adaptation following massive intestinal loss is characterized by increased villus height and crypt depth. Previously, we demonstrated that p21-null mice do not adapt after small bowel resection (SBR). As retinoblastoma protein (Rb) levels are elevated in p21-null crypt cells, we first sought to determine whether Rb is required for normal adaptation. Next, we tested whether Rb expression is responsible for blocked adaptation in p21-nulls.

Methods

Genetically manipulated mice and wild-type (WT) littermates underwent either 50% SBR or sham operation. The intestine was harvested at 3, 7, or 28 days later and intestinal adaptation was evaluated. Enterocytes were isolated and protein levels evaluated by Western blot and quantified by optical density.

Results

Rb-null mice demonstrated increased villus height, crypt depth, and proliferative rate at baseline, but there was no further increase following SBR. Deletion of one Rb allele lowered Rb expression and restored resection-induced adaptation responses in p21-null mice.

Conclusion

Rb is specifically required for resection-induced adaptation. Restoration of adaptation in p21-null mice by lowering Rb expression suggests a crucial mechanistic role for Rb in the regulation of intestinal adaptation by p21.

Presentations

Portions of this work were presented at the 6th Annual Academic Surgical Congress February 3, 2011 in Huntington Beach, CA, USA, and at The Society for Surgery of the Alimentary Tract, Digestive Diseases Week, May 10, 2011 in Chicago, IL, USA.

Grants

This work was supported by NIH 5T32CA00962122 (JAL, DW), the Digestive Diseases Research Core Center Morphology Core Grant #P30 DK52574, and RO1-DK 53234 (BW).