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.
γ-catenin, β-catenin, survivin, chronic myeloid leukemia (CML), CBP/p300, nuclear -catenin, chronic myeloid leukemia, CREB-Binding Protein, accel-erated phase, blast crisis, chronic myeloid, lentivirus, Lipofectamine Plus, tyrosine kinase domain, thrombopoietin, erythropoietin, immunoblotted, Chromatin Immunoprecipitation assay, granulocyte-macrophage, plakoglobin, hematopoeisis, erythroid, megakaryocytic formation, acute myeloid leukemia, inhibitor Imatinib, Immunoblotting, Bone Marrow, CREB binding protein, Imatinib
Edythe Broad Center for Stem Cell and Regenerative Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90033, USA.