The Gamma Catenin/CBP Complex Maintains Survivin Transcription in β-catenin Deficient/Depleted Cancer Cells
Abstract:Previously, we demonstrated that survivin expression is CBP/β-catenin/TCF-dependent. Now, using NCI-H28 cells, which harbor a homozygous deletion of β-catenin, we demonstrate that survivin transcription can similarly be mediated by nuclear γ-catenin. ICG-001, a specific inhibitor of binding to the N-terminus of CBP, effectively attenuates survivin expression. We demonstrate that γ-catenin by binding to TCF family members and specifically recruiting the coactivator CBP drives survivin transcription particularly in β-catenin-deficient cells. We also examined the relative expression of γ-catenin and β-catenin in 90 cases of chronic myeloid leukemia (CML) in a published gene expression microarray data base. A statistically significant negative correlation between γ-catenin and β-catenin was found in AP/BC cases (- 0.389, P = 0.006). Furthermore, in subsequent independent validation studies by qPCR in 28 CP and BC patients increased γ-catenin expression predominated in BC cases and was associated with concomitantly increased survivin expression. Gene expression was 3- and 6-fold greater in BC patients as compared to CP patients, for γ-catenin and survivin, respectively. Consistent with this observation, nuclear γ-catenin accumulation was evident in this population consistent with a potential transcriptional role. Combined treatment with imatinib mesylate (IM) and ICG-001 significantly inhibited colony formation in sorted CD34+ CML progenitors (survivin+/γ-cateninhigh/β-cateninlow) isolated from one BC and one AP patient resistant to IM. Therefore, we believe that the ability of ICG-001 to block both the CBP/γ-catenin interaction and the CBP/β-catenin interaction may have clinical significance in cancers in which γ-catenin plays a significant transcriptional role.
Keywords: Blast Crisis; Bone Marrow; CBP/p300; CREB binding protein; CREB-Binding Protein; Chromatin Immunoprecipitation assay; Imatinib; Immunoblotting; Lipofectamine Plus; accel-erated phase; acute myeloid leukemia; blast crisis; chronic myeloid; chronic myeloid leukemia; chronic myeloid leukemia (CML); erythroid; erythropoietin; granulocyte-macrophage; hematopoeisis; immunoblotted; inhibitor Imatinib; lentivirus; megakaryocytic formation; nuclear -catenin; plakoglobin; survivin; thrombopoietin; tyrosine kinase domain; β-catenin; γ-catenin
Document Type: Research Article
Publication date: 2011-02-01
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