The gamma catenin/CBP complex maintains survivin transcription in ß-catenin deficient/depleted cancer cells.
Curr Cancer Drug Targets
; 11(2): 213-25, 2011 Feb.
Article
de En
| MEDLINE
| ID: mdl-21158719
ABSTRACT
Previously, we demonstrated that survivin expression is CBP/ß-catenin/TCF-dependent. Now, using NCI-H28 cells, which harbor a homozygous deletion of ß-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 ß-catenin-deficient cells. We also examined the relative expression of γ-catenin and ß-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 ß-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)/ß-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/ß-catenin interaction may have clinical significance in cancers in which γ-catenin plays a significant transcriptional role.
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Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Transcription génétique
/
Protéine CBP
/
Protéines IAP
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Bêta-Caténine
/
Gamma-Caténine
Limites:
Animals
/
Humans
Langue:
En
Journal:
Curr Cancer Drug Targets
Sujet du journal:
ANTINEOPLASICOS
/
NEOPLASIAS
Année:
2011
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique