p27Kip1 nuclear localization and cyclin-dependent kinase inhibitory activity are regulated by glycogen synthase kinase-3 in human colon cancer cells

Q. Wang, Y. Zhou, X. Wang, B. M. Evers

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

The cellular mechanisms regulating intestinal differentiation are poorly understood. Sodium butyrate (NaBT), a short-chain fatty acid, increases p27Kip1 expression and induces cell cycle arrest associated with intestinal cell differentiation. Here, we show that treatment of intestinal-derived cells with NaBT induced G0/G1 arrest and intestinal alkaline phosphatase, a marker of differentiation, activity and mRNA expression; this induction was attenuated by inhibition of glycogen synthase kinase-3 (GSK-3). Moreover, treatment with NaBT increased the nuclear, but not the cytosolic, expression and activity of GSK-3β. NaBT decreased cyclin-dependent kinase CDK2 activity and induced p27Kip1 expression; inhibition of GSK-3 rescued NaBT-inhibited CDK2 activity and blocked NaBT-induced p27Kip1 expression in the nucleus but not in the cytoplasm. In addition, we demonstrate that NaBT decreased the expression of S-phase kinase-associated protein 2 (Skp2), and this decrease was attenuated by GSK-3 inhibition. Furthermore, NaBT increased p27Kip1 binding to CDK2, which was completely abolished by GSK-3 inhibition. Overexpression of an active form of GSK-3β reduced Skp2 expression, increased p27Kip1 in the nucleus and increased p27Kip1 binding to CDK2. Our results suggest that GSK-3 not only regulates nuclear p27Kip1 expression through the downregulation of nuclear Skp2 expression but also functions to regulate p27Kip1 assembly with CDK2, thereby playing a critical role in the G0/G1 arrest associated with intestinal cell differentiation.

Original languageEnglish
Pages (from-to)908-919
Number of pages12
JournalCell Death and Differentiation
Volume15
Issue number5
DOIs
StatePublished - May 2008

Bibliographical note

Funding Information:
Acknowledgements. We thank Wataru Ogawa (Kobe University School of Medicine, Chuo-ku, Japan) for the adenovirus encoding b-gal (Ad-b-gal) and the myristoylated activated form of Akt (Ad-Akt), Morris J Birnbaum (University of Pennsylvania School of Medicine, Philadelphia, PA) for adenovirus vector encoding HA-tagged catalytically active mutant of GSK3b (HA-GSK-3bS9A). We also thank Karen Martin for manuscript preparation and Tatsuo Uchida for statistical analysis. This work was supported by grants RO1 DK48498, R01 CA104748, R37 AG10885 and PO1 DK35608 from the National Institutes of Health.

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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