title: 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-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.
authors.affiliation: Childrens Hospital Los Angeles, Department of Pediatrics, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA. ymkim@chla.usc.edu
authors.forename: Yong-Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Vivian G
authors.initials: VG
authors.lastname: Oehler
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Gang
authors.forename: Cu
authors.initials: C
authors.lastname: Nguyen
authors.forename: David
authors.initials: D
authors.lastname: Masiello
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jerald
authors.initials: J
authors.lastname: Radich
authors.forename: Michael
authors.initials: M
authors.lastname: Kahn
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D011744:Pyrimidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000077022:Survivin; D051820:TCF Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D051185:gamma Catenin / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D050882:CREB-Binding Protein; D051034:Inhibitor of Apoptosis Proteins; D011744:Pyrimidinones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D000077022:Survivin; D051820:TCF Transcription Factors; D051176:beta Catenin; D051185:gamma Catenin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C107489:BIRC5 protein, human; C495270:CTNNB1 protein, human; C492448:ICG 001; C494364:Crebbp protein, mouse