Childrens Hospital Los Angeles, Department of Pediatrics, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
Curr Cancer Drug Targets. 2011 Feb;11(2):213-25. doi: 10.2174/156800911794328420.
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-catenin(high)/β-catenin(low)) 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.
先前，我们证实生存素的表达依赖于 CBP/β-连环蛋白/TCF。现在，我们使用 NCI-H28 细胞，其β-连环蛋白呈纯合缺失，证明生存素转录同样可以由核γ-连环蛋白介导。ICG-001 是一种特异性结合 CBP N 端的抑制剂，能有效减弱生存素的表达。我们证实γ-连环蛋白通过与 TCF 家族成员结合，并特异性募集共激活因子 CBP，驱动生存素转录，尤其是在β-连环蛋白缺陷的细胞中。我们还在已发表的基因表达微阵列数据库中检查了 90 例慢性髓性白血病（CML）中γ-连环蛋白和β-连环蛋白的相对表达。在 AP/BC 病例中，γ-连环蛋白与β-连环蛋白之间存在统计学上显著的负相关（-0.389，P = 0.006）。此外，在随后对 28 例 CP 和 BC 患者的独立 qPCR 验证研究中，在 BC 病例中，γ-连环蛋白表达增加占主导地位，并与同时增加的生存素表达相关。与 CP 患者相比，BC 患者的γ-连环蛋白和生存素的基因表达分别增加了 3 倍和 6 倍。与这一观察结果一致，在该人群中，核γ-连环蛋白的积累是明显的，这与潜在的转录作用一致。联合使用伊马替尼（IM）和 ICG-001 可显著抑制从一位对 IM 耐药的 BC 和一位 AP 患者中分离出的 CD34(+) CML 祖细胞（生存素（+）/γ-连环蛋白（高）/β-连环蛋白（低））中集落的形成。因此，我们认为 ICG-001 既能阻断 CBP/γ-连环蛋白相互作用，又能阻断 CBP/β-连环蛋白相互作用，这在γ-连环蛋白发挥重要转录作用的癌症中可能具有临床意义。
