Bcr is a negative regulator of the Wnt signalling pathway

Abstract

The Wnt signalling pathway can activate transcription of genes such as c-myc through b-catenin. Here, we describe the protein breakpoint cluster region, Bcr, as a negative regulator of this pathway. Bcr can form a complex with b-catenin and negatively regulate expression of c-Myc. Knockdown of Bcr by short interfering RNA relieves the block and activates expression of c-Myc. Expression of Bcr in the human colon carcinoma cell line HCT116, which has a high level of endogenous b-catenin, leads to reduced c-Myc expression. The negative effect is exerted by the amino terminus of Bcr, which does not harbour the kinase domain. Bcr-Abl, the oncogene protein expressed in chronic myelogenous leukaemia (CML), does not bind to b-catenin. It phosphorylates Bcr in the first exon sequence on tyrosines, which abrogates the binding of Bcr to b-catenin. The inhibitor of the Bcr-Abl tyrosine kinase, STI-571 or Gleevec, a drug against CML, reverses this effect. Our data contribute to the understanding of Bcr as a tumour suppressor in the Wnt signalling pathway, as well as in CML.

BCR-ABL-transformed GMP as myeloid leukemic stem cells

“…This mixed culture provides an experimental system to compare the pathobiological properties of BCR-ABL-transformed leukemic stem cells (GMP) and BCR-ABL-transformed leukemic cells (nonGMP). It has been shown that BCR-ABL kinase can directly activate ␤-catenin (21,22). Those studies observed a 2 to 3-fold activation of the Topflash reporter in transient cotransfection experiments employing established cell lines.…”

Kinase domain mutants of Bcr enhance Bcr-Abl oncogenic effects

“…Ress and Moelling (2005) showed that BCR expression reduces levels of b-catenin. Importantly, BcrAbl reverses these effects by tyrosine phosphorylation of Bcr first exon sequences (Ress and Moelling, 2005). We hypothesize that overexpression of wild-type Bcr inhibits tumorigenicity of Bcr-Abl þ cells by downregulation of b-catenin.…”

Different target range and cytotoxic specificity of adaphostin and 17-allylamino-17-demethoxygeldanamycin in imatinib-resistant and sensitive cell lines

“…We have shown that adaphostin lacks selectivity and inhibits expression of these proteins in cells lacking Bcr-Abl, so it is probable that this drug will affect non-leukaemic tissues as well as CML cells. Bcr has recently been shown to act as a tumour suppressor in the Wnt pathway 34 and downregulation of Akt may be especially problematic, as inhibitors of Akt-signalling have been responsible for occurrences of impaired glucose tolerance, hyperglycemia and type II diabetes (reviewed in Martelli et al 35 ). If these side effects prove to be significant, 17-AAG might actually be as potentially harmful as adaphostin, because it also causes downregulation of Akt.…”