Abstract
β-catenin has two different cellular functions: intercellular adhesion and transcriptional activity. The E3 ubiquitin ligase Siah1 causes ubiquitin-mediated degradation of the cytosolic β-catenin and therefore, impairs nuclear translocation and oncogenic function of β-catenin. However, the effect of Siah1 on the cell membrane bound β-catenin has not been studied. In this study, we identified that the carcinogenic bacterium H. pylori increased ETS2 transcription factor-mediated Siah1 protein expression in gastric cancer cells (GCCs) MKN45, AGS and Kato III. Siah1 protein level was also noticeably higher in gastric adenocarcinoma biopsy samples as compared to non-cancerous gastric epithelia. Siah1 knockdown significantly decreased invasiveness and migration of H. pylori-infected GCCs. Although, Siah1 could not increase degradation of the cytosolic β-catenin and its nuclear translocation, it enhanced degradation of the membrane-bound β-catenin in the infected GCCs. This loss of membrane-bound pool of β-catenin was not associated with the proteasomal degradation of E-cadherin. Thus, this work delineated the role of Siah1 in increasing invasiveness of H. pylori-infected GCCs.
Highlights
The seven in absentia homolog (Siah) family of E3 ubiquitin ligases are involved in the proteasomedependent degradation of target proteins
To study the Siah[1] protein level in H. pylori-infected gastric cancer cells (GCCs), MKN45 cells were infected with a cytotoxinassociated gene pathogenicity island-positive {cag Pathogenicity island (PAI)(+)} H. pylori strain 26695 at a multiplicity of infection (MOI) 100 and 200 for 3 h and 6 h
To assess the effect of H. pylori infection on Siah[1] transcription, MKN45 cells were infected with MOI 200 of H. pylori
Summary
Siah family of E3 ubiquitin ligases are involved in the proteasomedependent degradation of target proteins. Western blots of bead-bound proteins showed ETS2 binding with the siah[1] promoter EBS only in the infected cells (Figure 2b).
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