Loss of PHLPP protects against colitis by inhibiting intestinal epithelial cell apoptosis

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32 Scopus citations


A common feature of inflammatory bowel disease (IBD) is the loss of intestinal epithelial barrier function due to excessive apoptosis of intestinal epithelial cells (IECs). However, the molecular mechanism underlying increased IEC apoptosis remains unclear. Here, we investigated the role of PHLPP, a novel family of protein phosphatases, in regulating inflammation-induced IEC apoptosis in mouse models of colitis. Both Phlpp1 and Phlpp2 genes were deleted in mice. Compared with wild-type mice, PHLPP double knockout (DKO) mice were protected from colitis induced by DSS as demonstrated by lower histopathological scores, and this reduced susceptibility to colitis was associated with decreased apoptosis and increased Akt activity in IECs in vivo. In addition, epithelial organoids derived from PHLPP DKO mice were more resistant to inflammation-induced apoptosis while inhibition of Akt activity abolished the protective effect of PHLPP-loss. Furthermore, we found that PHLPP expression was significantly reduced in IECs following the induction of colitis by DSS and in human IBD patient samples. This inflammation-induced downregulation of PHLPP was partially blocked by treating cells with a proteasome inhibitor. Taken together, our results indicated that proteasome-mediated degradation of PHLPP at the onset of inflammation plays an important role in protecting IEC injury by inhibiting apoptosis.

Original languageEnglish
Pages (from-to)2013-2023
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number10
StatePublished - Oct 1 2015

Bibliographical note

Funding Information:
This work was supported by NIH R01CA133429 (TG) and P20GM103527 (TG). The studies were supported by Biospecimen and Tissue Procurement and Biostatistics Shared Resources of the University of Kentucky Markey Cancer Center ( P30CA177558 ). We thank Dana Napier at the Biospecimen and Tissue Procurement facility for her help with preparation and sectioning of paraffin-embedded mouse tissues. The Biostatistics Shared Resource Facility provided assistance with statistical analysis.

Publisher Copyright:
© 2015 Elsevier B.V.


  • Akt
  • Inflammatory bowel disease
  • Intestine epithelial cell apoptosis
  • Knockout mouse

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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