β-catenin inhibits promyelocytic leukemia protein tumor suppressor function in colorectal cancer cells.
Loss of promyelocytic leukemia protein (PML) nuclear body (NB) formation has been reported in colorectal and other solid tumors. However, genetic alteration of PML is rarely observed in these tumors; the exact mechanisms that mediate loss of PML function are not known.We previously used a comprehensive shotgun mass spectrometry approach ... to identify PML as 1 of 70 proteins that coimmunoprecipitate with anti-T-cell factor 4 in DLD-1 and HCT116 colorectal cancer cell lines; we investigated the effects of altered β-catenin expression on PML function in these cells.β-catenin specifically interacted with the product of PML transcript variant IV (PML-IV) through the armadillo repeat domain of β-catenin. Overexpression of β-catenin in colorectal cancer cells disrupted the subcellular compartmentalization of PML-IV, whereas knockdown of β-catenin restored formation of PML-NB. Modification of PML by the small ubiquitin-related modifier (SUMO) is required for proper assembly of PML-NB. β-catenin inhibited Ran-binding protein 2-mediated SUMOylation of PML-IV.β-catenin interacts with PML isoform IV and disrupts PML-IV function and PML-NB formation by inhibiting Ran-binding protein 2-mediated SUMO modification of PML-IV. These findings indicate the involvement of a posttranslational mechanism in disruption of PML-NB organization in cancer cells and provide more information about the oncogenic functions of β-catenin.
Mesh Terms:
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Nucleus, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, HEK293 Cells, HeLa Cells, Humans, Lysine, Molecular Chaperones, Nuclear Pore Complex Proteins, Nuclear Proteins, Protein Binding, Protein Isoforms, RNA Interference, Small Ubiquitin-Related Modifier Proteins, Sumoylation, Transcription Factors, Transcriptional Activation, Transfection, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Wnt Signaling Pathway, beta Catenin
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Nucleus, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, HEK293 Cells, HeLa Cells, Humans, Lysine, Molecular Chaperones, Nuclear Pore Complex Proteins, Nuclear Proteins, Protein Binding, Protein Isoforms, RNA Interference, Small Ubiquitin-Related Modifier Proteins, Sumoylation, Transcription Factors, Transcriptional Activation, Transfection, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Wnt Signaling Pathway, beta Catenin
Gastroenterology
Date: Mar. 01, 2012
PubMed ID: 22155184
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