Helicobacter pylori increases proteasome-mediated degradation of p27kip1 in gastric epithelial cells

Hidetoshi Eguchi, Nicole Herschenhous, Noriyoshi Kuzushita, Steven F. Moss

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40 Citations (Scopus)

Abstract

Helicobacter pylori infection is associated with increased gastric epithelial cell turnover and is a risk factor for noncardia gastric cancer. H. pylori reduces the expression of p27 protein, a cyclin-dependent kinase inhibitor of the G1 to S-phase cell cycle transition and gastric tumor suppressor gene. Although cell cycle dysregulation associated with decreased p27 may contribute to gastric carcinogenesis, how H. pylori reduces p27 in gastric epithelial cells remains unknown. In the present study, we investigated the mechanisms of the p27 decrease, using AGS and MKN28 gastric epithelial cells cocultured with H. pylori strains under conditions of defined cell cycle distribution. The expression of p27 protein was reduced by H. pylori in a dose- and time-dependent manner. Northern blot and pulse-chase analyses revealed that this reduction was not regulated at a transcriptional level but by accelerated p27 degradation via a proteasome-dependent pathway. Despite up-regulation of the proteasome-dependent degradation of p27 protein, neither threonine 187-phosphorylated p27 nor skp2 (the ubiquitin ligase for p27) were increased. Furthermore, H. pylori impaired p27 ubiquitination and did not increase global proteasomal function. These results indicate that H. pylori increases the degradation of p27 through a proteasomal pathway distinct from the physiological pathway that degrades p27 during cell cycle progression. Putative virulence genes of H. pylori (cagA, cagE, or vacA) played no role in reducing p27 expression. Increased degradation of p27 by H. pylori through a proteasome-dependent, ubiquitin-independent pathway may contribute to the increased risk of gastric cancer associated with chronic H. pylori infection.

Original languageEnglish
Pages (from-to)4739-4746
Number of pages8
JournalCancer Research
Volume63
Issue number15
Publication statusPublished - Aug 1 2003

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Eguchi, H., Herschenhous, N., Kuzushita, N., & Moss, S. F. (2003). Helicobacter pylori increases proteasome-mediated degradation of p27kip1 in gastric epithelial cells. Cancer Research, 63(15), 4739-4746.