β-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia

Joseph H. Sellin, Yu Wang, Pomila Singh, Shahid Umar

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Utilizing the Citrobacter rodentium (CR)-induced transmissible murine colonic hyperplasia (TMCH) model, we provide mechanistic basis of changes in β-catenin/APC/CKIe{open} leading to progression and/or regression of hyperplasia in vivo. In response to CR-induced TMCH, crypt lengths increased significantly between days 6-27 post-infection, followed by a steep decline by day 34. β-Cat45/total β-catenin were elevated on day 1 post-infection, preceding changes in crypt length, and persisted for 27 days before declining by day 34. Importantly, cellular CKIe{open} and β-catenin co-immunoprecipitated and exhibited remarkable parallel changes in kinetics during hyperplasia/regression phases. β-catenin, phosphorylated at Ser33,37 and Thr41 (β-cat33,37/41), was low till day 12, followed by gradual increase until day 27 before declining by day 34. GSK-3β exhibited significant Ser9-phosphorylation/inactivation at days 6-12 with partial recovery at days 27-34. Wild type (wt) APC (p312) levels increased at day 6 with transient proteolysis/truncation to p130 form between days 12 and 15; p312 reappeared by day 19 and returned to baseline by day 34. The kinetics of β-Cat45/β-catenin nuclear accumulation and acetylation (Ac-β-CatLys49) from days 6 to 27, followed by loss of phosphorylation/acetylation by day 34 was almost identical; Tcf-4 co-immunoprecipitated with β-Cat45/β-catenin and localized immunohistochemically to β-Cat41/45-positive regions leading to elevated cyclin D1 expression, during the hyperproliferative, but not regression phases of TMCH. CKIe{open} mediated phosphorylation of β-Cat45, resulting in stabilization/nuclear translocation of β-Cat45 may be critical for maintaining proliferation at days 6-27. Reversal of GSK-3β phosphorylation and APC changes may be equally critical during the regression phase from days 27 to 34.

Original languageEnglish (US)
Pages (from-to)97-109
Number of pages13
JournalExperimental Cell Research
Volume315
Issue number1
DOIs
StatePublished - Jan 1 2009

Fingerprint

Catenins
Epithelium
Hyperplasia
Phenotype
Citrobacter rodentium
Phosphorylation
Glycogen Synthase Kinase 3
Acetylation
Cyclin D1
Infection
Proteolysis

Keywords

  • Bacterial infection
  • Colon
  • Colon cancer
  • Hyperplasia
  • Hyperproliferation
  • In vivo
  • Murine

ASJC Scopus subject areas

  • Cell Biology

Cite this

β-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia. / Sellin, Joseph H.; Wang, Yu; Singh, Pomila; Umar, Shahid.

In: Experimental Cell Research, Vol. 315, No. 1, 01.01.2009, p. 97-109.

Research output: Contribution to journalArticle

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N2 - Utilizing the Citrobacter rodentium (CR)-induced transmissible murine colonic hyperplasia (TMCH) model, we provide mechanistic basis of changes in β-catenin/APC/CKIe{open} leading to progression and/or regression of hyperplasia in vivo. In response to CR-induced TMCH, crypt lengths increased significantly between days 6-27 post-infection, followed by a steep decline by day 34. β-Cat45/total β-catenin were elevated on day 1 post-infection, preceding changes in crypt length, and persisted for 27 days before declining by day 34. Importantly, cellular CKIe{open} and β-catenin co-immunoprecipitated and exhibited remarkable parallel changes in kinetics during hyperplasia/regression phases. β-catenin, phosphorylated at Ser33,37 and Thr41 (β-cat33,37/41), was low till day 12, followed by gradual increase until day 27 before declining by day 34. GSK-3β exhibited significant Ser9-phosphorylation/inactivation at days 6-12 with partial recovery at days 27-34. Wild type (wt) APC (p312) levels increased at day 6 with transient proteolysis/truncation to p130 form between days 12 and 15; p312 reappeared by day 19 and returned to baseline by day 34. The kinetics of β-Cat45/β-catenin nuclear accumulation and acetylation (Ac-β-CatLys49) from days 6 to 27, followed by loss of phosphorylation/acetylation by day 34 was almost identical; Tcf-4 co-immunoprecipitated with β-Cat45/β-catenin and localized immunohistochemically to β-Cat41/45-positive regions leading to elevated cyclin D1 expression, during the hyperproliferative, but not regression phases of TMCH. CKIe{open} mediated phosphorylation of β-Cat45, resulting in stabilization/nuclear translocation of β-Cat45 may be critical for maintaining proliferation at days 6-27. Reversal of GSK-3β phosphorylation and APC changes may be equally critical during the regression phase from days 27 to 34.

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